5-amido-indole-2-carboxamide derivatives

ABSTRACT

The present invention relates to compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein G and R 1  to R 5  and R 12  are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

PRIORITY TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 11/784,041,filed Apr. 5, 2007 which claims the benefit of European PatentApplication No. 06112562.1, filed Apr. 12, 2006, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is concerned with novel 5-amido-2-carboxamideindole derivatives, their manufacture, pharmaceutical compositionscontaining them and their use as medicaments. The active compounds ofthe present invention are useful in treating obesity and otherdisorders.

In a preferred embodiment, the present invention relates to compounds ofthe general formula

and pharmaceutically acceptable salts thereof.

The compounds of formula I are antagonists and/or inverse agonists atthe histamine 3 receptor (H3 receptor).

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND

Histamine(2-(4-imidazolyl)ethylamine) is one of the aminergicneurotransmitters which is widely distributed throughout the body, e.g.the gastrointestinal tract (Burks 1994 in Johnson L. R. ed., Physiologyof the Gastrointestinal Tract, Raven Press, NY, pp. 211-242). Histamineregulates a variety of digestive pathophysiological events like gastricacid secretion, intestinal motility (Leurs et al., Br J. Pharmacol.1991, 102, pp 179-185), vasomotor responses, intestinal inflammatoryresponses and allergic reactions (Raithel et al., Int. Arch. AllergyImmunol. 1995, 108, 127-133). In the mammalian brain, histamine issynthesized in histaminergic cell bodies which are found centrally inthe tubero-mammillary nucleus of the posterior basal hypothalamus. Fromthere, the histaminergic cell bodies project to various brain regions(Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagakiet al., J. Comp. Neurol 1988, 273, 283-300).

According to current knowledge, histamine mediates all its actions inboth the CNS and the periphery through four distinct histaminereceptors, the histamine H1, H2H3 and H4 receptors.

H3 receptors are predominantly localized in the central nervous system(CNS). As an autoreceptor H3 receptors constitutively inhibit thesynthesis and secretion of histamine from histaminergic neurons (Arranget al., Nature 1983, 302, 832-837; Arrang et al., Neuroscience 1987, 23,149-157). As heteroreceptors, H3 receptors also modulate the release ofother neurotransmitters such as acetylcholine, dopamine, serotonin andnorepinephrine among others in both the central nervous system and inperipheral organs, such as lungs, cardiovascular system andgastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982,107, 919-923; Blandina et al. in The Histamine H3 Receptor (Leurs R Land Timmermann H eds, 1998, pp 27-40, Elsevier, Amsterdam, TheNetherlands). H3 receptors are constitutively active, meaning that evenwithout exogenous histamine, the receptor is tonically activated. In thecase of an inhibitory receptor such as the H3 receptor, this inherentactivity causes tonic inhibition of neurotransmitter release. Thereforeit may be important that a H3R antagonist would also have inverseagonist activity to both block exogenous histamine effects and to shiftthe receptor from its constitutively active (inhibitory) form to aneutral state.

The wide distribution of H3 receptors in the mammalian CNS indicates thephysiological role of this receptor. Therefore the therapeutic potentialas a novel drug development target in various indications has beenproposed.

The administration of H3R ligands—as antagonists, inverse agonists,agonists or partial agonists—may influence the histamine levels or thesecretion of neurotransmitters in the brain and the periphery and thusmay be useful in the treatment of several disorders. Such disordersinclude obesity, (Masaki et al; Endocrinol. 2003, 144, 2741-2748;Hancock et al., European J. of Pharmacol. 2004, 487, 183-197),cardiovascular disorders such as acute myocardial infarction, dementiaand cognitive disorders such as attention deficit hyperactivity disorder(ADHD) and Alzheimer's disease, neurological disorders such asschizophrenia, depression, epilepsy, Parkinson's disease, and seizuresor convulsions, sleep disorders, narcolepsy, pain, gastrointestinaldisorders, vestibular dysfunction such as Morbus Meniere, drug abuse andmotion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-11).

SUMMARY OF THE INVENTION

In an embodiment of the present invention, provided is a compound offormula I:

wherein:R¹ is selected from the group consisting of

-   -   lower alkyl, lower alkenyl, lower alkinyl,    -   cycloalkyl, lower cycloalkylalkyl,    -   lower hydroxyalkyl,    -   lower alkoxyalkyl,    -   lower alkylsulfanylalkyl,    -   lower dialkylaminoalkyl,    -   lower dialkylcarbamoylalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, lower        halogenalkoxy and lower hydroxyalkyl,    -   lower phenylalkyl wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,    -   lower heteroarylalkyl wherein the heteroaryl ring may be        unsubstituted or substituted with one or two groups        independently selected from lower alkyl, halogen, lower alkoxy        and lower hydroxyalkyl, lower heterocyclylalkyl wherein the        heterocyclyl ring may be unsubstituted or substituted with one        or two groups selected from lower alkyl and halogen, and    -   7-oxa-bicyclo[2.2.1]heptyl;        R² is selected from the group consisting of hydrogen,    -   lower alkyl, lower alkenyl, lower alkinyl,    -   cycloalkyl, lower cycloalkylalkyl,    -   lower hydroxyalkyl, lower alkoxyalkyl,    -   lower alkylsulfanylalkyl,    -   lower dialkylaminoalkyl,    -   lower dialkylcarbamoylalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, lower        halogenalkoxy and lower hydroxyalkyl,    -   lower phenylalkyl wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,    -   lower heteroarylalkyl wherein the heteroaryl ring may be        unsubstituted or substituted with one or two groups        independently selected from lower alkyl, halogen, lower alkoxy        and lower hydroxyalkyl, and    -   lower heterocyclylalkyl wherein the heterocycly ring may be        unsubstituted or substituted with one or two lower alkyl groups;        or        R¹ and R² together with the nitrogen atom to which they are        attached form a 4-, 5-, 6- or 7-membered saturated or partly        unsaturated heterocyclic ring optionally containing a further        heteroatom selected from oxygen or sulfur, a sulfinyl group or a        sulfonyl group, said heterocyclic ring        being unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, halogen, lower        halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy,        oxo, phenyl, benzyl, pyridyl and carbamoyl, or        being condensed with a phenyl ring, said phenyl ring being        unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, lower alkoxy and        halogen, or        R¹ and R² together with the nitrogen atom to which they are        attached form a group selected from 1-oxa-8-aza-spiro[4.5]decyl,        1,4-dioxa-8-aza-spiro[4.5]decyl and [1,4]oxazepan-7-one;        R³ is selected from the group consisting of hydrogen, lower        alkyl, cycloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower        halogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower        cyanoalkyl, lower alkylsulfonyl,    -   phenylsulfonyl wherein the phenyl ring may be unsubstituted or        substituted with one to three groups independently selected from        lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and        lower hydroxyalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, cyano,        morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower        halogenalkyl, lower halogenalkoxy, lower hydroxyalkyl, lower        alkylsulfonyl and lower alkylsulfonylamino, benzodioxolyl,    -   lower phenylalkyl, wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, cyano, morpholinyl, lower alkoxy,        lower alkoxycarbonyl, lower halogenalkyl, lower halogenalkoxy,        lower hydroxyalkyl, lower alkylsulfonyl and lower        alkylsulfonylamino, and    -   heteroaryl unsubstituted or substituted with one or two groups        independently selected from lower alkyl, lower alkoxy, cyano,        morpholinyl and halogen;        R⁴, R¹² and R⁵ are hydrogen, or        one of R⁴, R¹² and R⁵ is halogen and the other ones are        hydrogen;        G is a group selected from

whereinR⁶ is selected from the group consisting of lower alkyl, cycloalkyl,lower cycloalkylalkyl and a heterocyclic ring containing oxygen;R⁷ is hydrogen; or R⁶ and R⁷ together are —(CH₂)_(p)—, wherein p is 3 or4, and are bonded to each other to form a ring together with the carbonor nitrogen atom to which they are attached;n is 1 or 2;m is 1 or 2;R⁸ is hydrogen or lower heterocyclylalkyl;R⁹ is hydrogen or —NR¹⁰R¹¹;R¹⁰ and R¹¹ independently from each other are lower alkyl or togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen or sulfur;R¹³ is hydrogen or —NR¹⁰R¹¹;and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, provided is a processfor the manufacture of a compound according to formula I, comprising thesteps of:

reacting a compound of formula II

wherein R¹, R², R⁴, R¹² and R⁵ are as defined herein before and R³ ishydrogen, with an amine of the formula IIIA or IIIB

wherein R⁶, R⁷, R⁸, R⁹, R¹³, m and n are as defined herein before, inthe presence of a coupling reagent under basic conditions to obtain acompound of the formula IA

wherein R¹, R², R⁴, R¹², R⁵ and G are as defined herein before and R³ ishydrogen, and optionally transferring into a compound of formula IB

wherein R³ is a group as defined herein before other than hydrogen, andif desired,converting the compound obtained into a pharmaceutically acceptable acidaddition salt.

In a further embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I as well as apharmaceutically acceptable carrier and/or adjuvant.

In a yet another embodiment of the present invention, provided is amethod for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors, comprising the step ofadministering a therapeutically active amount of a compound according toformula I to a human being or animal in need thereof.

In a still further embodiment of the present invention, provided is amethod for the treatment or prevention of obesity in a human being oranimal, comprising the step of administering a therapeutically effectiveamount of a compound of formula I in combination or association with atherapeutically effective amount of a compound selected from the groupconsisting of a lipase inhibitor, an anorectic agent, a selectiveserotonin reuptake inhibitor, and an agent that stimulates metabolism ofbody fat.

In a yet still another embodiment of the present invention, provided isa method of treatment or prevention of type II diabetes in a human beingor animal, comprising the step of administering a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of an anti-diabeticagent.

DETAILED DESCRIPTION

The present invention provides for selective, directly acting H3receptor antagonists respectively inverse agonists. Suchantagonists/inverse agonists are useful as therapeutically activesubstances, particularly in the treatment and/or prevention of diseaseswhich are associated with the modulation of H3 receptors.

In the present description the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to twenty carbon atoms,preferably one to sixteen carbon atoms, more preferably one to tencarbon atoms.

The term “lower alkyl” or “C₁-C₈-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with 1to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms. Examples ofstraight-chain and branched C₁-C₈ alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls,the isomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl and ethyl and most preferred methyl.

The term “lower alkenyl” or “C₂₋₈-alkenyl”, alone or in combination,signifies a straight-chain or branched hydrocarbon radical comprising anolefinic bond and up to 8, preferably up to 6, particularly preferred upto 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.A preferred example is 2-propenyl.

The term “lower alkinyl” or “C₂₋₈-alkinyl”, alone or in combination,signifies a straight-chain or branched hydrocarbon residue comprising atriple bond and up to 8, preferably up to 6, particularly preferred upto 4 carbon atoms. Examples of alkinyl groups are ethinyl, 1-propinyl,or 2-propinyl. A preferred example is 2-propinyl.

The term “cycloalkyl” or “C₃-C₇-cycloalkyl” denotes a saturatedcarbocyclic group containing from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Especially preferred are cyclobutyl and cyclopentyl.

The term “lower cycloalkylalkyl” or “C₃₋₇-cycloalkyl-C₁₋₈-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by cycloalkyl. Apreferred example is cyclopropylmethyl.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Examples oflower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.

The term “alkoxy” or “lower alkoxy” refers to the group R′—O—, whereinR′ is lower alkyl and the term “lower alkyl” has the previously givensignificance. Examples of lower alkoxy groups are e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy andtert.-butoxy, preferably methoxy and ethoxy and most preferred methoxy.

The term “lower alkoxyalkyl” or “C₁-C₈-alkoxy-C₁-C₈-alkyl” refers tolower alkyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkyl groups is replaced by an alkoxy group,preferably methoxy or ethoxy. Among the preferred lower alkoxyalkylgroups are 2-methoxyethyl or 3-methoxypropyl.

The term “alkylsulfanyl” or “C₁₋₈-alkylsulfanyl” refers to the groupR′—S—, wherein R′ is lower alkyl and the term “lower alkyl” has thepreviously given significance. Examples of alkylsulfanyl groups are e.g.methylsulfanyl or ethylsulfanyl.

The term “lower alkylsulfanylalkyl” or “C₁₋₈-alkylsulfanyl-C₁₋₈-alkyl”refers to lower alkyl groups as defined above wherein at least one ofthe hydrogen atoms of the lower alkyl groups is replaced by analkylsulfanyl group, preferably methylsulfanyl. An example for apreferred lower alkylsulfanylalkyl group is 2-methylsulfanylethyl.

The term “alkylsulfonyl” or “lower alkylsulfonyl” refers to the groupR′—S(O)₂—, wherein R′ is lower alkyl and the term “lower alkyl” has thepreviously given significance. Examples of alkylsulfonyl groups are e.g.methylsulfonyl or ethylsulfonyl.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “lower halogenalkyl” or “halogen-C₁-C₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a halogen atom, preferablyfluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,trifluoroethyl, fluoromethyl and chloromethyl, with trifluoromethyl or2,2,2-trifluoro ethyl being especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁-C₈-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,preferably fluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy,fluormethoxy and chloromethoxy, with trifluoromethoxy being especiallypreferred.

The term “dialkylamino” refers to the group —NR′R″, wherein R′ and R″are lower alkyl and the term “lower alkyl” has the previously givensignificance. A preferred dialkylamino group is dimethylamino.

The term “alkylsulfonylamino” or “lower alkylsulfonylamino” refers tothe group R′—S(O)₂—NH—, wherein R′ is lower alkyl and the term “loweralkyl” has the previously given significance.

Examples of alkylsulfonyl groups are e.g. methylsulfonylamino orethylsulfonylamino.

The term “lower dialkylaminoalkyl” or “C₁₋₈-dialkylamino-C₁₋₈-alkyl”refers to lower alkyl groups as defined above wherein at least one ofthe hydrogen atoms of the lower alkyl group is replaced by adialkylamino group, preferably dimethylamino. A preferred lowerdialkylaminoalkyl group is 3-dimethylaminopropyl.

The term “carbamoyl” refers to the group —CO—NH₂.

The term “dialkylcarbamoyl” or “C₁₋₈-dialkylcarbamoyl” refers to thegroup —CO—NR′R″ wherein R′ and R″ are lower alkyl and the term “loweralkyl” has the previously given significance. A preferreddialkylcarbamoyl group is dimethylcarbamoyl.

The term “lower dialkylcarbamoylalkyl” or“C₁₋₈-dialkylcarbamoyl-C₁₋₈-alkyl” refers to lower alkyl groups asdefined above wherein at least one of the hydrogen atoms of the loweralkyl group is replaced by a dialkylcarbamoyl group as defined hereinbefore. A preferred lower dialkylcarbamoylalkyl groups isdimethylcarbamoylmethyl.

The term “lower alkanoyl” refers to the group —CO—R′, wherein R′ islower alkyl and the term “lower alkyl” has the previously givensignificance. Preferred is a group —CO—R′, wherein R′ is methyl, meaningan acetyl group.

The term “lower phenylalkyl” or “phenyl-C₁₋₈-alkyl” to lower alkylgroups as defined above wherein at least one of the hydrogen atoms ofthe lower alkyl group is replaced by a phenyl group. Preferred lowerphenylalkyl groups are benzyl or phenethyl.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise one, two or three atoms selected from nitrogen, oxygenand/or sulphur. Examples of heteroaryl groups are e.g. furyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl,isothiazolyl, oxazolyl, imidazolyl, or pyrrolyl. Especially preferredare pyridyl and pyrimidinyl.

The term “lower heteroarylalkyl” or “heteroaryl-C₁₋₈-alkyl” refers tolower alkyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a heteroaryl group asdefined above.

The term “heterocyclyl” refers to a saturated or partly unsaturated 5-or 6-membered ring which can comprise one, two or three atoms selectedfrom nitrogen, oxygen and/or sulphur. Examples of heterocyclyl ringsinclude piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl,tetrahydrofuryl, oxetanyl, dihydropyranyl, tetrahydropyranyl, andthiomorpholinyl. Preferred heterocyclyl groups are pyrrolidinyl andpiperidinyl.

The term “lower heterocyclylalkyl” or “heterocyclyl-C₁₋₈-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by a heterocyclylgroup as defined above.

The term “form a 4-, 5-, 6- or 7-membered heterocyclic ring optionallycontaining a further heteroatom selected from oxygen or sulfur” refersto a N-heterocyclic ring, which may optionally contain a further oxygenor sulfur atom, such as azetidinyl, pyrrolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, or azepanyl. A “4-, 5-, 6- or 7-memberedheterocyclic ring containing a sulfinyl group or a sulfonyl group” meansa N-heterocyclic ring that contains a —S(O)— group or a —SO₂— group, forexample 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl. Theheterocyclic ring may be unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, halogen,halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo,phenyl, benzyl, pyridyl and carbamoyl. The heterocyclic ring may also becondensed with a phenyl ring, said phenyl ring being unsubstituted orsubstituted by one, two or three groups independently selected fromlower alkyl, lower alkoxy and halogen. Examples for such condensedheterocyclic rings are 3,4-dihydro-1H-isoquinoline or1,3-dihydroisoindole.

The term “heterocyclic ring containing oxygen” refers preferably tocyclic ether rings such as oxetane, tetrahydrofurane andtetrahydropyrane.

The term “oxo” means that a C-atom of the heterocyclic ring may besubstituted by ═O, thus meaning that the heterocyclic ring may containone or more carbonyl (—CO—) groups.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared form addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space and have one or more asymmetriccarbon atoms are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images are termed“enantiomers”, or sometimes optical isomers.

In detail, the present invention relates to compounds of the generalformula

whereinR¹ is selected from the group consisting of

-   -   lower alkyl, lower alkenyl, lower alkinyl,    -   cycloalkyl, lower cycloalkylalkyl,    -   lower hydroxyalkyl,    -   lower alkoxyalkyl,    -   lower alkylsulfanylalkyl,    -   lower dialkylaminoalkyl,    -   lower dialkylcarbamoylalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, lower        halogenalkoxy and lower hydroxyalkyl,    -   lower phenylalkyl wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,    -   lower heteroarylalkyl wherein the heteroaryl ring may be        unsubstituted or substituted with one or two groups        independently selected from lower alkyl, halogen, lower alkoxy        and lower hydroxyalkyl,    -   lower heterocyclylalkyl wherein the heterocyclyl ring may be        unsubstituted or substituted with one or two groups selected        from lower alkyl and halogen, and    -   7-oxa-bicyclo[2.2.1]heptyl;        R² is selected from the group consisting of hydrogen,    -   lower alkyl, lower alkenyl, lower alkinyl,    -   cycloalkyl, lower cycloalkylalkyl,    -   lower hydroxyalkyl, lower alkoxyalkyl,    -   lower alkylsulfanylalkyl,    -   lower dialkylaminoalkyl,    -   lower dialkylcarbamoylalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, lower        halogenalkoxy and lower hydroxyalkyl,    -   lower phenylalkyl wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,    -   lower heteroarylalkyl wherein the heteroaryl ring may be        unsubstituted or substituted with one or two groups        independently selected from lower alkyl, halogen, lower alkoxy        and lower hydroxyalkyl, and    -   lower heterocyclylalkyl wherein the heterocycly ring may be        unsubstituted or substituted with one or two lower alkyl groups;        or        R¹ and R² together with the nitrogen atom to which they are        attached form a 4-, 5-, 6- or 7-membered saturated or partly        unsaturated heterocyclic ring optionally containing a further        heteroatom selected from oxygen or sulfur, a sulfinyl group or a        sulfonyl group, said heterocyclic ring        being unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, halogen, lower        halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy,        oxo, phenyl, benzyl, pyridyl and carbamoyl, or        being condensed with a phenyl ring, said phenyl ring being        unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, lower alkoxy and        halogen, or        R¹ and R² together with the nitrogen atom to which they are        attached form a group selected from 1-oxa-8-aza-spiro[4.5]decyl,        1,4-dioxa-8-aza-spiro[4.5]decyl and [1,4]oxazepan-7-one;        R³ is selected from the group consisting of hydrogen, lower        alkyl, cycloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower        halogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower        cyanoalkyl, lower alkylsulfonyl,    -   phenylsulfonyl wherein the phenyl ring may be unsubstituted or        substituted with one to three groups independently selected from        lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and        lower hydroxyalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, cyano,        morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower        halogenalkyl, lower halogenalkoxy, lower hydroxyalkyl, lower        alkylsulfonyl and lower alkylsulfonylamino, benzodioxolyl,    -   lower phenylalkyl, wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, cyano, morpholinyl, lower alkoxy,        lower alkoxycarbonyl, lower halogenalkyl, lower halogenalkoxy,        lower hydroxyalkyl, lower alkylsulfonyl and lower        alkylsulfonylamino, and    -   heteroaryl unsubstituted or substituted with one or two groups        independently selected from lower alkyl, lower alkoxy, cyano,        morpholinyl and halogen;        R⁴, R¹² and R⁵ are hydrogen, or        one of R⁴, R¹² and R⁵ is halogen and the other ones are        hydrogen;        G is a group selected from

whereinR⁶ is selected from the group consisting of lower alkyl, cycloalkyl,lower cycloalkylalkyl and a heterocyclic ring containing oxygen;R⁷ is hydrogen; or R⁶ and R⁷ together are —(CH₂)_(p)—, wherein p is 3 or4, and are bonded to each other to form a ring together with the carbonor nitrogen atom to which they are attached;n is 1 or 2;m is 1 or 2;R⁸ is hydrogen or lower heterocyclylalkyl;R⁹ is hydrogen or —NR¹⁰R¹¹;R¹⁰ and R¹¹ independently from each other are lower alkyl or togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen or sulfur;R¹³ is hydrogen or —NR¹⁰R¹¹;and pharmaceutically acceptable salts thereof.

Preferred are compounds of formula I according to the present invention,wherein R¹ is selected from the group consisting of

lower alkyl, lower alkenyl, lower alkinyl,cycloalkyl, lower cycloalkylalkyl,lower hydroxyalkyl,lower alkoxyalkyl,lower alkylsulfanylalkyl,lower dialkylaminoalkyl,lower dialkylcarbamoylalkyl,phenyl unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, lower halogenalkoxyand lower hydroxyalkyl,lower phenylalkyl wherein the phenyl ring may be unsubstituted orsubstituted with one to three groups independently selected from loweralkyl, halogen, lower alkoxy and lower hydroxyalkyl,lower heteroarylalkyl wherein the heteroaryl ring may be unsubstitutedor substituted with one or two groups independently selected from loweralkyl, halogen, lower alkoxy and lower hydroxyalkyl,lower heterocyclylalkyl wherein the heterocyclyl ring may beunsubstituted or substituted with one or two groups selected from loweralkyl and halogen, and7-oxa-bicyclo[2.2.1]heptyl; andR² is hydrogen or lower alkyl.

More preferably, compounds of formula I according to the invention arethose, wherein

R¹ is selected from the group consisting ofcycloalkyl,phenyl unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, lower halogenalkoxyand lower hydroxyalkyl,lower phenylalkyl wherein the phenyl ring may be unsubstituted orsubstituted with one to three groups independently selected from loweralkyl, halogen, lower alkoxy and lower hydroxyalkyl, andlower heterocyclylalkyl wherein the heterocyclyl ring may beunsubstituted or substituted with one or two groups selected from loweralkyl and halogen; andR² is hydrogen or lower alkyl.

Further preferred compounds of formula I according the present inventionare those, wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6- or 7-membered saturated or partlyunsaturated heterocyclic ring optionally containing a further heteroatomselected from oxygen or sulfur, a sulfinyl group or a sulfonyl group,said heterocyclic ring being unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, halogen, lowerhalogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo,phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenylring, said phenyl ring being unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, lower alkoxy andhalogen, or wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a group selected from1-oxa-8-aza-spiro[4.5]decyl, 1,4-dioxa-8-aza-spiro[4.5]decyl and[1,4]oxazepan-7-one.

More preferably, the compounds of formula I according to the inventionare those, wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a heterocyclic ring selected from the groupconsisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine,azepane, piperazine, azetidine, thiomorpholine, 1,1-dioxothiomorpholineand 3,6-dihydro-2H-pyridine, said heterocyclic ring being unsubstitutedor substituted by one, two or three groups independently selected fromlower alkyl, halogen, lower halogenalkyl, cyano, hydroxy, lowerhydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl,or being condensed with a phenyl ring, said phenyl ring beingunsubstituted or substituted by one, two or three groups independentlyselected from lower alkyl, lower alkoxy and halogen, or wherein R¹ andR² together with the nitrogen atom to which they are attached form agroup selected from 1-oxa-8-aza-spiro[4.5]decyl,1,4-dioxa-8-aza-spiro[4.5]decyl and [1,4]oxazepan-7-one.

Especially preferred are compounds of formula I according to theinvention, wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a heterocyclic ring selected from the groupconsisting of morpholine, thiomorpholine, 1,1-dioxothiomorpholine,pyrrolidine, piperidine and azepane, said heterocyclic ring beingunsubstituted or substituted by one, two or three groups independentlyselected from lower alkyl, halogen, lower halogenalkyl, cyano, hydroxy,lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl andcarbamoyl, or being condensed with a phenyl ring, said phenyl ring beingunsubstituted or substituted by one, two or three groups independentlyselected from lower alkyl, lower alkoxy and halogen, or wherein R¹ andR² together with the nitrogen atom to which they are attached form a1,4-dioxa-8-aza-spiro[4.5]decyl group.

Most preferably, compounds of formula I according to the invention arethose, wherein R¹ and R² together with the nitrogen atom to which theyare attached form a heterocyclic ring selected from the group consistingof morpholine, thiomorpholine, 1,1-dioxothio-morpholine, pyrrolidine,piperidine and 4,4-difluoropiperidinyl.

Preferred are furthermore compounds of formula I according to thepresent invention, wherein R³ is selected from the group consisting of

hydrogen, lower alkyl, cycloalkyl,lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lowercycloalkylalkyl,lower cyanoalkyl, lower alkylsulfonyl,phenyl unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, cyano, morpholinyl,lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl, lowerhalogenalkoxy, lower hydroxyalkyl, lower alkylsulfonyl and loweralkylsulfonylamino, benzodioxolyl,lower phenylalkyl, wherein the phenyl ring may be unsubstituted orsubstituted with one to three groups independently selected from loweralkyl, halogen, cyano, morpholinyl, lower alkoxy, lower alkoxycarbonyl,lower halogenalkyl, lower halogenalkoxy, lower hydroxyalkyl, loweralkylsulfonyl and lower alkylsulfonylamino, andheteroaryl unsubstituted or substituted with one or two groupsindependently selected from lower alkyl, lower alkoxy, cyano,morpholinyl and halogen.

One group of preferred compounds of formula I of the invention arethose, wherein R³ is selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lowerhalogenalkyl, lower cycloalkylalkyl, lower cyanoalkyl and loweralkylsulfonyl, with those compounds, wherein R³ is lower alkyl or lowerhalogenalkyl, being especially preferred. Compounds of formula I,wherein R³ is hydrogen, are also preferred.

A further group of preferred compounds are compounds of formula I of theinvention, wherein R³ is phenyl unsubstituted or substituted with one tothree groups independently selected from lower alkyl, halogen, cyano,morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl,lower halogenalkoxy, lower alkylsulfonyl and lower alkylsulfonylamino,benzodioxolyl, or lower phenylalkyl, wherein the phenyl ring may beunsubstituted or substituted with one to three groups independentlyselected from halogen, cyano or lower halogenalkyl, with those compoundsof formula I, wherein R³ is unsubstituted phenyl or phenyl substitutedwith one to three groups independently selected from halogen, cyano orlower halogenalkyl, being especially preferred.

Another group of preferred compounds of formula I are those, wherein R³is heteroaryl selected from pyridyl or pyrimidinyl, said heteroarylbeing unsubstituted or substituted with one or two groups independentlyselected from lower alkyl, lower alkoxy, cyano, morpholinyl and halogen.

Compounds of formula I are preferred, wherein R¹² is hydrogen.

Furthermore, compounds of formula I according to the invention arepreferred, wherein R⁴, R¹² and R⁵ are hydrogen.

Preferred compounds of formula I of the present invention are alsothose, wherein G signifies

wherein R⁶ is selected from the group consisting of lower alkyl,cycloalkyl, lower cycloalkylalkyl and a heterocyclic ring containingoxygen and R⁷ is hydrogen;or R⁶ and R⁷ together are —(CH₂)_(p)—, wherein p is 3 or 4, and arebonded to each other to form a ring together with the carbon or nitrogenatom to which they are attached;and n is 1 or 2.

Especially preferred are compounds of formula I according to theinvention, wherein R⁶ is selected from the group consisting of loweralkyl, cycloalkyl and lower cycloalkylalkyl and R⁷ is hydrogen, withthose compounds of formula I, wherein R⁶ is lower alkyl or cycloalkyl,being more preferred, and with compounds of formula I, wherein R⁶ isselected from the group consisting of isopropyl, cyclobutyl andcyclopentyl.

Another group of preferred compounds of formula I according to theinvention are those, wherein R⁶ and R⁷ together are —(CH₂)_(p)—, whereinp is 3 or 4, and are bonded to each other to form a ring together withthe carbon or nitrogen atom to which they are attached, with thosecompounds of formula I, wherein p is 3, being especially preferred.

Furthermore, compounds of formula I, wherein n is 1, are preferred.

Also preferred are compounds of formula I of the present invention,wherein G signifies

wherein m is 1 or 2, R⁸ is hydrogen or lower heterocyclylalkyl, R⁹ ishydrogen or —NR¹⁰R¹¹, R¹³ is hydrogen or —NR¹⁰R¹¹, and R¹⁰ and R¹¹independently from each other are lower alkyl or together with thenitrogen atom to which they are attached form a 5- or 6-memberedsaturated heterocyclic ring optionally containing a further heteroatomselected from nitrogen, oxygen or sulfur.

More preferably, R¹³ is hydrogen. Especially preferred are compounds offormula I, wherein R¹² and R¹³ are hydrogen.

Especially preferred are also compounds of formula I according to theinvention, wherein R⁸ is hydrogen, R⁹ is —NR¹⁰R¹¹, R¹³ is hydrogen andR¹⁰ and R¹¹ independently from each other are lower alkyl or togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen or sulfur, with thosecompounds of formula I, wherein R¹⁰ and R¹¹ independently from eachother are lower alkyl, being more preferred. Most preferably, R¹⁰ andR¹¹ are methyl.

One group of preferred compounds of formula I are those, wherein m is 1.

Compounds of formula I, wherein m is 2, are also preferred.

Also especially preferred are compounds of formula I according to theinvention, wherein R⁸ is lower heterocyclylalkyl and R⁹ is hydrogen.More preferably, lower heterocyclylalkyl is lower pyrrolidinylalkyl,most preferably pyrrolidinylmethyl.

The present invention specifically relates to compounds of formula Ihaving the general formula

whereinR¹ is selected from the group consisting of

-   -   lower alkyl, lower alkenyl, lower alkinyl,    -   cycloalkyl, lower cycloalkylalkyl,    -   lower hydroxyalkyl,    -   lower alkoxyalkyl,    -   lower alkylsulfanylalkyl,    -   lower dialkylaminoalkyl,    -   lower dialkylcarbamoylalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, lower        halogenalkoxy and lower hydroxyalkyl,    -   lower phenylalkyl wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,    -   lower heteroarylalkyl wherein the heteroaryl ring may be        unsubstituted or substituted with one or two groups        independently selected from lower alkyl, halogen, lower alkoxy        and lower hydroxyalkyl,    -   lower heterocyclylalkyl wherein the heterocyclyl ring may be        unsubstituted or substituted with one or two groups selected        from lower alkyl and halogen, and    -   7-oxa-bicyclo[2.2.1]heptyl;        R² is selected from the group consisting of hydrogen,    -   lower alkyl, lower alkenyl, lower alkinyl,    -   cycloalkyl, lower cycloalkylalkyl,    -   lower hydroxyalkyl, lower alkoxyalkyl,    -   lower alkylsulfanylalkyl,    -   lower dialkylaminoalkyl,    -   lower dialkylcarbamoylalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, lower        halogenalkoxy and lower hydroxyalkyl,    -   lower phenylalkyl wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,    -   lower heteroarylalkyl wherein the heteroaryl ring may be        unsubstituted or substituted with one or two groups        independently selected from lower alkyl, halogen, lower alkoxy        and lower hydroxyalkyl, and    -   lower heterocyclylalkyl wherein the heterocycly ring may be        unsubstituted or substituted with one or two lower alkyl groups;        or        R¹ and R² together with the nitrogen atom to which they are        attached form a 4-, 5-, 6- or 7-membered saturated or partly        unsaturated heterocyclic ring optionally containing a further        heteroatom selected from oxygen or sulfur, a sulfinyl group or a        sulfonyl group, said heterocyclic ring        being unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, halogen, lower        halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy,        oxo, phenyl, benzyl, pyridyl and carbamoyl, or        being condensed with a phenyl ring, said phenyl ring being        unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, lower alkoxy and        halogen, or        R¹ and R² together with the nitrogen atom to which they are        attached form a group selected from 1-oxa-8-aza-spiro[4.5]decyl,        1,4-dioxa-8-aza-spiro[4.5]decyl and [1,4]oxazepan-7-one;        R³ is selected from the group consisting of hydrogen, lower        alkyl, cycloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower        halogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower        cyanoalkyl, lower alkylsulfonyl,    -   phenylsulfonyl wherein the phenyl ring may be unsubstituted or        substituted with one to three groups independently selected from        lower alkyl, halogen, lower alkoxy, lower halogenalkoxy and        lower hydroxyalkyl,    -   phenyl unsubstituted or substituted with one to three groups        independently selected from lower alkyl, halogen, cyano,        morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower        halogenalkyl, lower halogenalkoxy, lower hydroxyalkyl,    -   lower alkylsulfonyl and lower alkylsulfonylamino, benzodioxolyl,    -   lower phenylalkyl, wherein the phenyl ring may be unsubstituted        or substituted with one to three groups independently selected        from lower alkyl, halogen, cyano, morpholinyl, lower alkoxy,        lower alkoxycarbonyl, lower halogenalkyl, lower halogenalkoxy,        lower hydroxyalkyl, lower alkylsulfonyl and lower        alkylsulfonylamino, and    -   heteroaryl unsubstituted or substituted with one or two groups        independently selected from lower alkyl, lower alkoxy, cyano,        morpholinyl and halogen;        R⁴ and R⁵ are hydrogen, or        one of R⁴ and R⁵ is halogen and the other one is hydrogen;        G is a group selected from

whereinR⁶ is selected from the group consisting of lower alkyl, cycloalkyl,lower cycloalkylalkyl and a heterocyclic ring containing oxygen;R⁷ is hydrogen; or R⁶ and R⁷ together are —(CH₂)_(p)—, wherein p is 3 or4, and are bonded to each other to form a ring together with the carbonor nitrogen atom to which they are attached;n is 1 or 2;m is 1 or 2;R⁸ is hydrogen or lower heterocyclylalkyl;R⁹ is hydrogen or —NR¹⁰R¹¹;R¹⁰ and R¹¹ independently from each other are lower alkyl or togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen or sulfur;and pharmaceutically acceptable salts thereof.

Preferred compounds of formula I of the present invention are thefollowing:

-   [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-piperidin-1-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methyl-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-hydroxy-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-thiomorpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(3-fluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone,-   5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    benzyl-methyl-amide,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-piperidin-1-yl-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methyl-piperidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   (4-hydroxy-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-thiomorpholin-4-yl-methanone,-   (3-fluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone,-   5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    benzylamide,-   5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    benzyl-methyl-amide,-   5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    cyclopentylamide,-   azepan-1-yl-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   azepan-1-yl-[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (3,4-dihydro-1H-isoquinolin-2-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    (4-fluoro-phenyl)-amide,-   5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    (4-fluoro-phenyl)-methyl-amide,-   5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    (2,6-dimethyl-phenyl)-amide,-   5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    (2,4,6-trimethyl-phenyl)-amide,-   5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid    (2-fluoro-phenyl)-amide,-   (4-cyclopentyl-piperazin-1-yl)-[2-(2,3-dihydro-indole-1-carbonyl)-1H-indol-5-yl]-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone,-   [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclohexyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [1-cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-acetonitrile,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-methanesulfonyl-1-indol-2-yl]-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-acetonitrile,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-methanesulfonyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(morpholine-4-carbonyl)-indol-1-yl]-acetonitrile,-   (4-cyclopentyl-piperazin-1-yl)-[1-methanesulfonyl-2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone,-   [1-benzyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-p-tolyl-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [1-(4-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   4-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile-   [1-(3-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone-   3-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [1-benzyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [1-(4-chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-(3-chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(4-fluoro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(3-fluoro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-p-tolyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(3-methoxy-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   4-[5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzoic    acid methyl ester,-   3-[5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzoic    acid ethyl ester,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(1,1-dioxo-1,1-thiomorpholine-4-carbonyl)-indol-1-yl]-acetonitrile,-   4-[5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   3-[5-(4-cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   3-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzoic    acid ethyl ester,-   4-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzoic    acid methyl ester,-   (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-benzyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-phenyl-ethyl)-1H-indol-2-yl]-methanone,-   cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic    acid (3-fluoro-oxetan-3-ylmethyl)-amide,-   [1-(3-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   3-[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (1,1-dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(4-chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [1-(3-chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(4-fluoro-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(3-fluoro-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-p-tolyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [1-(4-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   4-[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (1,1-dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   (1,1-dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   4-[5-(4-isopropyl-piperazine-1-carbonyl)-2-(morpholine-4-carbonyl)-indol-1-yl]-benzonitrile,-   (4,4-difluoro-piperidin-1-yl)-[1-(3-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (1,1-dioxo-1,l,6-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-phenyl-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-[1-(2-fluoro-phenyl)-ethyl]-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [1-cyclobutylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-((R)-1-phenyl-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-((S)-1-phenyl-ethyl)-1H-indol-2-yl]-methanone,-   [1-(3-chloro-phenyl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   3-[5-(4-cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-(4-chloro-phenyl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   4-[5-(4-cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-cyclopropylmethyl-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-methanone,-   [1-(3-chloro-phenyl)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   3-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(3-chloro-phenyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   3-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(4-chloro-phenyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   4-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-cyclopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-methyl-1-phenyl-ethyl)-1H-indol-2-yl]-methanone,-   [1-cyclopropylmethyl-5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   [1-cyclobutyl-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(4-methanesulfonyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3,5-difluoro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-(6-chloro-pyridin-3-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-benzo[1,3]dioxol-5-yl-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(4-morpholin-4-yl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(6-morpholin-4-yl-pyridin-3-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(2-methoxy-pyrimidin-5-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   N-{4-[5-(4-cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-phenyl}-methanesulfonamide,-   [1-cyclopropylmethyl-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-(2-methoxy-ethyl)-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [1-cyclobutylmethyl-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-(2-hydroxy-ethyl)-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-(2-chloro-pyridin-4-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-(3-chloro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-([1,4′]bipiperidinyl-1′-carbonyl)-1-(6-chloro-pyridin-3-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-cyclopropylmethyl-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-(3-chloro-phenyl)-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(6-chloro-pyridin-3-yl)-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-cyclopropylmethyl-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [1-(3-chloro-phenyl)-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(6-chloro-pyridin-3-yl)-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   [1-(3-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [1-cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone,-   (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone,-   [1-(3-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone,-   (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-2-(1,1-dioxothiomorpholine-4-carbonyl)-indol-1-yl]-acetonitrile,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3-fluoro-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [1-(3-chloro-phenyl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   3-[5-(4-cyclobutyl-piperazine-1-carbonyl)-2-(1,1-dioxothiomorpholine-4-carbonyl)-indol-1-yl]-benzonitrile,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3-methanesulfonyl-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethoxy-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [1-(6-chloro-pyridin-3-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(4-methanesulfonyl-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   (1,1-dioxothiomorpholin-4-yl)-[1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   [2-(1,1-dioxothiomorpholine-4-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-acetonitrile,-   (1,1-dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-methanone,-   (1,1-dioxothiomorpholin-4-yl)-[1-(3-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   (1,1-dioxothiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-methanesulfonyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone-   [1-(6-chloro-pyridin-3-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone,-   (1,1-dioxothiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-methanesulfonyl-phenyl)-1H-indol-2-yl]-methanone,-   (1,1-dioxothiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-pyrimidin-5-yl-1H-indol-2-yl]-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [6-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [4-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [6-chloro-1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [4-chloro-1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [6-chloro-1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [7-chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [7-chloro-1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-methanone,-   [5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-(4-sec-butyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (1,1-dioxo-thiomorpholin-4-yl)-[1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone,-   (1,1-dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone,-   [5-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,    and pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds:

-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [1-(3-chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   (1,1-dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone,-   [5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-(3-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone,-   3-[5-(4-cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclobutyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,-   (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone,-   (1,1-dioxo-thiomorpholin-4-yl)-[1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone,    and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds offormula I and the pharmaceutically acceptable esters of the compounds offormula I individually constitute preferred embodiments of the presentinvention.

Compounds of formula I may form acid addition salts with acids, such asconventional pharmaceutically acceptable acids, for examplehydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartarate,and methanesulphonate. Preferred are the hydrochloride salts. Alsosolvates and hydrates of compounds of formula I and their salts formpart of the present invention.

Compounds of formula I can have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises

reacting a compound of formula II

wherein R¹, R², R⁴, R¹² and R⁵ are as defined herein before and R³ ishydrogen, with an amine of the formula IIIA or IIIB

wherein R⁶, R⁷, R⁸, R⁹, R¹³, m and n are as defined herein before, inthe presence of a coupling reagent under basic conditions to obtain acompound of the formula IA

wherein R¹, R², R⁴, R⁵, R¹² and G are as defined herein before and R³ ishydrogen, and optionally transferring into a compound of formula IB

wherein R³ is a group as defined herein before other than hydrogen,and if desired,converting the compound obtained into a pharmaceutically acceptable acidaddition salt.

Appropriate coupling reagents are for example N,N-carbonyldiimidazole(CDI) or 1-hydroxy-1,2,3-benzotriazole (HOBT). The reaction is carriedout in a suitable solvent such as for example dimethylformamide (DMF) ordioxane in the presence of an appropriate base. Preferred is a base suchas triethylamine or diisopropylethylamine.

Transferring into a compound of formula IB means treating the compoundof formula IA with a suitable base in a suitable solvent under anhydrousconditions (e.g. sodium hydride in DMF) and reacting the intermediateanion with an alkylating or acylating agent R³-X, wherein X signifies aleaving group such as e.g. iodide, bromide, methanesulfonate orchloride, to obtain a compound of formula IB wherein R³ signifies loweralkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lowercycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower alkylsulfonylor phenylsulfonyl, or alternatively, transferring into a compound offormula IB means reacting a compound of formula IA with an optionallysubstituted phenylboronic acid using an appropriate catalyst (e.g.copper(II) acetate) and base (e.g. pyridine) in a suitable solvent like,e.g. dichloromethane, to obtain a compounds of formula IB where R³signifies a phenyl or a substituted phenyl group.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. The preparation of compounds of formula I of thepresent invention may be carried out in sequential or convergentsynthetic routes. Syntheses of the invention are shown in the followingschemes. The skills required for carrying out the reaction andpurification of the resulting products are known to those skilled in theart. The substituents and indices used in the following description ofthe processes have the significance given herein before unless indicatedto the contrary.

Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

Compounds of the general formula IA and IB can be prepared according toscheme 1 by a process where the 2-carbethoxyindole-5-carboxylic acid offormula A (prepared according to, e.g. Lindwall, H. G.; Mantell, G. J.;J. Org. Chem. 1953, 18, 345) is first reacted with an amine of formulaIII (either commercially available or accessible by methods described inreferences or by methods known in the art) to give intermediate B. Thecoupling of carboxylic acids with amines (either commercially availableor accessible by methods described in references or by methods known inthe art) is widely described in literature (e.g. Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2nd Edition,Richard C. Larock. John Wiley & Sons, New York, N.Y. 1999) and can beaccomplished by employing the usage of coupling reagents such as, e.g.N,N-carbonyldiimidazole (CDI), 1-hydroxy-1,2,3-benzotriazole (HOBT) orO-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU)in a suitable solvent like, e.g. dimethylformamide (DMF) or dioxane inthe presence of an appropriate base (e.g. triethylamine ordiisopropylethylamine). The ester functionality in intermediates B iscleaved under basic (e.g. with lithium hydroxide in polar solvents suchas, e.g. methanol, water or THF or mixtures of said solvents) or underacidic conditions (e.g. using concentrated hydrochloric acid in THF) andsubsequent transformation of the resulting either lithium orhydrochloride salt of intermediate C to compounds of the general formulaIA applying the before-mentioned methods.

Intermediates of formula IB can be obtained for example throughtreatment of intermediates of formula IA with a suitable base in asuitable solvent under anhydrous conditions (e.g. sodium hydride in DMF)and reacting the intermediate anion with an alkylating or acylatingagent R³-X such as, e.g. methyl iodide, 2-bromopropane,2,2,2-trifluoroethyl-methanesulfonate, methanesulfonyl- orphenylsulfonylchloride. In those cases R³ signifies a methyl,trifluoromethyl, isopropyl or an alkyl- or arylsulfonyl group and Xsignifies a leaving group such as, e.g. iodide, bromide,methanesulfonate or chloride. Compounds of formula IB where R³ signifiesa phenyl or a substituted phenyl group can be synthesized by processesknown to those skilled in the art and described in literature (e.g. W.W. K. R. Mederski et. al, Tetrahedron, 1999, 55, 12757). For example,intermediates of formula IA are reacted with an optionally substitutedphenylboronic acid using an appropriate catalyst (e.g. copper(II)acetate) and base (e.g. pyridine) in a suitable solvent like, e.g.dichloromethane. R^(a) in Scheme 1 is an alkyl group, preferably a loweralkyl group, preferably methyl or ethyl.

Compounds of general formula IC can be prepared according to Scheme 2 bya process involving the reaction of 5-bromoindole-2-carboxylic acid withan amine of formula IV (either commercially available or accessible bymethods described in references or by methods known in the art) to giveintermediate E. The coupling of carboxylic acids with amines is widelydescribed in literature (e.g. Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2nd Edition, Richard C. Larock.John Wiley & Sons, New York, N.Y. 1999) and can be accomplished byemploying the usage of coupling reagents (e.g. N,N-carbonyldiimidazole).

Intermediates of formula F can be obtained for example through treatmentof intermediates of formula E with a suitable base in a suitable solventunder anhydrous conditions (e.g. sodium hydride in tetrahydrofuran) andreacting the intermediate anion with an alkylating or acylating agentR³-X such as, e.g. methyl iodide, 2-bromopropane,2,2,2-trifluoroethyl-methanesulfonate, methanesulfonyl- orphenylsulfonylchloride. In those cases R³ signifies a methyl,trifluoromethyl, isopropyl or an alkyl- or arylsulfonyl group and Xsignifies a leaving group such as, e.g. iodide, bromide,methanesulfonate or chloride. Compounds of formula F where R³ signifiesa phenyl or a substituted phenyl group can be synthesized by processesknown to those skilled in the art and described in literature (e.g. W.W. K. R. Mederski et. al, Tetrahedron, 1999, 55, 12757). For example,intermediates of formula E are reacted with an optionally substitutedphenylboronic acid using an appropriate catalyst (e.g. copper(II)acetate) and base (e.g. pyridine) in a suitable solvent (e.g.dichloromethane).

Intermediates of formula G can be obtained for example through treatmentof intermediates of formula F with a palladium source (e.g. palladiumacetate) and suitable ligand (e.g. 1,3-(diphenylphosphino)ferrocene) ina suitable solvent or solvent mixture (e.g. 1:1 v:vdimethylsulfoxide/ethanol) under carbon monoxide atmosphere (at, e.g. 1Atmosphere) by processes known to those skilled in the art and describedin literature (e.g. Kumar, K. Org. Letters 2004, 6, 4).

The ester functionality in intermediates G is cleaved under basic (e.g.with lithium hydroxide in polar solvents such as, e.g. methanol, wateror THF or mixtures of said solvents) or under acidic conditions (e.g.using concentrated hydrochloric acid in THF) and subsequenttransformation of the resulting either lithium salt or salt-freeintermediate H to compounds of the general formula IC applying thebefore-mentioned methods.

In cases of substituents G1 where the substituent R⁶ is not alreadypresent in the corresponding piperidine or homopiperidine substituentIV, R⁶ can be introduced as exemplified in Scheme 3. Amide coupling ofintermediates J with protected (e.g. with a tert-butoxycarbonylprotective group) and optionally substituted piperidines orhomopiperidines leads to intermediates K, which in turn can bedeprotected (e.g. a tert-butoxycarbonyl group by using, e.g.trifluoroacetic acid in dichloromethane) to give intermediates L.Alkylation of the free amine functionality in intermediates K byemploying methods described in references or by methods known in the artsuch as, e.g. reductive amination (e.g. F. Zaragoza, et. al, J. Med.Chem. 2004, 47, 2833) gives compounds of the general formula IA.

The compounds of formula I can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, e.g. racemates, optically pure diastereomers,mixtures of diastereomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The optically active forms can be obtained forexample by resolution of the racemates, by asymmetric synthesis orasymmetric chromatography (chromatography with a chiral adsorbents oreluant).

Alternatively, compounds of general structure IB may be preparedaccording to scheme 4. Intermediates of formula B′ can be obtained forexample through treatment of intermediates of formula B with a suitablebase in a suitable solvent under anhydrous conditions (e.g. sodiumhydride in DMF or caesium carbonate in acetonitrile) and reacting theintermediate anion with an alkylating or acylating agent R³-X such as,e.g. methyl iodide, 2-bromopropane, isopropylmethanesulfonate,2,2,2-trifluoroethyl-methanesulfonate, methanesulfonyl- orphenylsulfonylchloride. In those cases R³ signifies a methyl,trifluoromethyl, isopropyl or an alkyl- or arylsulfonyl group and Xsignifies a leaving group such as, e.g. iodide, bromide,methanesulfonate or chloride. Compounds of formula B′ where R³ signifiesa phenyl or a substituted phenyl group can be synthesized by processesknown to those skilled in the art and described in literature (e.g. W.W. K. R. Mederski et. al, Tetrahedron, 1999, 55, 12757). For example,intermediates of formula B are reacted with an optionally substitutedphenylboronic acid using an appropriate catalyst (e.g. copper(II)acetate) and base (e.g. pyridine) in a suitable solvent like, e.g.dichloromethane. R^(a) in Scheme 4 is an alkyl group, preferably a loweralkyl group, preferably methyl or ethyl.

As described above, the compounds of formula I of the present inventioncan be used as medicaments for the treatment and/or prevention ofdiseases which are associated with the modulation of H3 receptors.

In this context, the expression ‘diseases associated with the modulationof H3 receptors’ means diseases which can be treated and/or prevented bymodulation of H3 receptors. Such diseases encompass, but are not limitedto, obesity, metabolic syndrome (syndrome X), neurological diseasesincluding Alzheimer's disease, dementia, age-related memory dysfunction,mild cognitive impairment, cognitive deficit, attention deficithyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness,schizophrenia, depression, addiction, motion sickness and sleepdisorders including narcolepsy, and other diseases including asthma,allergy, allergy-induced airway responses, congestion, chronicobstructive pulmonary disease and gastro-intestinal disorders.

In a preferable aspect, the expression ‘diseases associated withmodulation of H3 receptors’ relates to obesity, metabolic syndrome(syndrome X), and other eating disorders, with obesity being especiallypreferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutically active substances, particularly as therapeutic activesubstances for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are associated with themodulation of H3 receptors, which method comprises administering atherapeutically active amount of a compound of formula I to a humanbeing or animal. A method for the treatment and/or prevention of obesityis preferred.

The invention further relates to the use of compounds of formula I asdefined above for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors.

In addition, the invention relates to the use of compounds of formula Ias defined above for the preparation of medicaments for the treatmentand/or prevention of diseases which are associated with the modulationof H3 receptors. The use of compounds of formula I as defined above forthe preparation of medicaments for the treatment and/or prevention ofobesity is preferred.

Furthermore, the present invention relates to the use of a compound offormula I for the manufacture of a medicament for the treatment andprevention of obesity in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

It is a further preferred embodiment of the present invention to providea method for the treatment or prevention of obesity and obesity relateddisorders which comprises administration of a therapeutically effectiveamount of a compound according to formula I in combination orassociation with a therapeutically effective amount of other drugs forthe treatment of obesity or eating disorders so that together they giveeffective relief. Suitable other drugs include, but are not limited to,anorectic agents, lipase inhibitors, selective serotonin reuptakeinhibitors (SSRI) and agents that stimulate metabolism of body fat.Combinations or associations of the above agents may be encompassingseparate, sequential or simultaneous administration.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO 99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to tetrahydrolipstatin.Administration of a therapeutically effective amount of a compoundaccording to formula I in combination or association with atherapeutically effective amount of tetrahydrolipstatin is especiallypreferred.

Tetrahydrolipstatin (orlistat) is a known compound useful for thecontrol or prevention of obesity and hyperlipidemia. See, U.S. Pat. No.4,598,089, issued Jul. 1, 1986, which also discloses processes formaking orlistat and U.S. Pat. No. 6,004,996, which discloses appropriatepharmaceutical compositions. Further suitable pharmaceuticalcompositions are described for example in International PatentApplications WO 00/09122 and WO 00/09123. Additional processes for thepreparation of orlistat are disclosed in European Patent ApplicationsPublication Nos. 0 185 359, 0 189 577, 0 443 449, and 0 524 495.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, APD356, aminorex,amphechloral, amphetamine, axokine, benzphetamine, bupropion,chlorphentermine, clobenzorex, cloforex, clominorex, clortermine,CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine,SLV319, SNAP 7941, SR147778 (Surinabant), steroidal plant extract (e.g.P57) and TM30338 and pharmaceutically acceptable salts thereof.

Most preferable anorectic agents are sibutramine, rimonabant andphentermine.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable agents that stimulate metabolism of body fat include, but arenot limited to, growth hormone agonist (e.g. AOD-9604).

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a compound selected from the group consistingof a lipase inhibitor, an anorectic agent, a selective serotoninreuptake inhibitor, and an agent that stimulates metabolism of body fat,is also an embodiment of the present invention.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a lipase inhibitor, preferably withtetrahydrolipstatin, is also an embodiment of the present invention.

It is a further preferred object to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of a lipaseinhibitor, particularly, wherein the lipase inhibitor istetrahydrolipstatin. Also an embodiment of the invention is the methodas described above for the simultaneous, separate or sequentialadministration of a compound according to formula I and a lipaseinhibitor, particularly tetrahydrolipstatin.

It is a further preferred embodiment to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of an anti-diabeticagent.

The term “anti-diabetic agent” refers to compounds selected from thegroup consisting of 1) PPARγ agonists such as pioglitazone (actos) orrosiglitazone (avandia), and the like; 2) biguanides such as metformin(glucophage), and the like; 3) sulfonylureas such as glibenclamide,glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta), andthe like; 4) nonsulfonylureas such as nateglinide (starlix), repaglimide(prandin), and the like; 5) PPARα/γ agonists such as GW-2331, and thelike 6) DPP-IV-inhibitors such as LAF-237 (vildagliptin), MK-0431,BMS-477118 (saxagliptin) or GSK23A and the like; 7) Glucokinaseactivators such as the compounds disclosed in e.g. WO 00/58293 A1, andthe like; 8) α-Glucosidase inhibitors such as acarbose (precose) ormiglitol (glyset), and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of ananti-diabetic agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of Type II diabetes in a patient who isalso receiving treatment with an anti-diabetic agent is also anembodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of dyslipidemias in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofa lipid lowering agent.

The term “lipid lowering agent” refers to compounds selected from thegroup consisting of 1) bile acid sequestrants such as cholestyramine(questran), colestipol (colestid), and the like; 2) HMG-CoA reductaseinhibitors such as atorvastatin (lipitor), cerivastatin (baycol),fluvastatin (lescol), pravastatin (pravachol), simvastatin (zocor) andthe like; 3) cholesterol absorption inhibitors such as ezetimibe, andthe like; 4) CETP inhibitors such as torcetrapib, JTT 705, and the like;5) PPARα-agonists such as beclofibrate, gemfibrozil (lopid), fenofibrate(lipidil), bezafibrate (bezalip), and the like; 6) lipoprotein synthesisinhibitors such as niacin, and the like; and 7) niacin receptor agonistssuch as nicotinic acid, and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of a lipidlowering agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of dyslipidemias in a patient who isalso receiving treatment with a lipid lowering agent, is also anembodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of hypertension in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofan anti-hypertensive agent.

The term “anti-hypertensive agent” or “blood-pressure lowering agent”refers to compounds selected from the group consisting of 1)Angiotensin-converting Enzyme (ACE) Inhibitors including benazepril(lotensin), captopril (capoten), enalapril (vasotec), fosinopril(monopril), lisinopril (prinivil, zestril), moexipril (univasc),perindopril (coversum), quinapril (accupril), ramipril (altace),trandolapril (mavik), and the like; 2) Angiotensin II ReceptorAntagonists including candesartan (atacand), eprosartan (teveten),irbesartan (avapro), losartan (cozaar), telmisartan (micadisc),valsartan (diovan), and the like; 3) Adrenergic Blockers (peripheral orcentral) such as the beta-adrenergic blockers including acebutolol(sectrol), atenolol (tenormin), betaxolol (kerlone), bisoprolol(zebeta), carteolol (cartrol), metoprolol (lopressor; toprol-XL),nadolol (corgard), penbutolol (levatol), pindolol (visken), propranolol(inderal), timolol (blockadren) and the like; alpha/beta adrenergicblockers including carvedilol (coreg), labetalol (normodyne), and thelike; alpha-1 adrenergic blockers including prazosin (minipress),doxazosin (cardura), terazosin (hytrin), phenoxybenzamine (dibenzyline),and the like; peripheral adrenergic-neuronal blockers includingguanadrel (hylorel), guanethidine (ismelin), reserpine (serpasil), andthe like; alpha-2 adrenergic blockers including a-methyldopa (aldomet),clonidine (catapres), guanabenz (wytensin), guanfacine (tenex), and thelike; 4) Blood Vessel Dilators (Vasodilators) including hydralazine(apresoline), minoxidil (lonitren), clonidine (catapres), and the like;5) Calcium Channel Blockers including amlodipine (norvasc), felodipine(plendil), isradipine (dynacirc), nicardipine (cardine sr), nifedipine(procardia, adalat), nisoldipine (sular), diltiazem (cardizem),verapamil (isoptil), and the like; 6) Diuretics such as thiazides andthiazides-like agents, including hydrochlorothiazide (hydrodiuril,microzide), chlorothiazide (diuril), chlorthalidone (hygroton),indapamide (lozol), metolazone (mykrox), and the like; loop diuretics,such as bumetanide (bumex) and furosemide (lasix), ethacrynic acid(edecrin), torsemide (demadex), and the like; potassium-sparingdiuretics including amiloride (midamor), triamterene (dyrenium),spironolactone (aldactone), and the tiamenidine (symcor) and the like;7) Tyrosine Hydroxylase Inhibitors, including metyrosine (demser), andthe like; 8) Neutral Endopeptidase Inhibitors, including BMS-186716(omapatrilat), UK-79300 (candoxatril), ecadotril (sinorphan), BP-1137(fasidotril), UK-79300 (sampatrilat) and the like; and 9) EndothelinAntagonists including tezosentan (RO0610612), A308165, and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of aanti-hypertensive agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of hypertension in a patient who isalso receiving treatment with an anti-hypertensive agent, is also anembodiment of the present invention.

As described above, the compounds of formula I and theirpharmaceutically acceptable salts possess valuable pharmacologicalproperties. Specifically, it has been found that the compounds of thepresent invention are good histamine 3 receptor (H3R) antagonists and/orinverse agonists.

The following test was carried out in order to determine the activity ofthe compounds of formula (I).

Binding Assay with ³H—(R)α-Methylhistamine

Saturation binding experiments were performed using HR3-CHO membranesprepared as described in Takahashi, K, Tokita, S., Kotani, H. (2003) J.Pharmacol. Exp. Therapeutics 307, 213-218.

An appropriate amount of membrane (60 to 80 μg protein/well) wasincubated with increasing concentrations of ³H(R)α-Methylhistaminedi-hydrochloride (0.10 to 10 nM). Non specific binding was determinedusing a 200 fold excess of cold (R)α-Methylhistamine dihydrobromide (500nM final concentration). The incubation was carried out at roomtemperature (in deep-well plates shaking for three hours). The finalvolume in each well was 250 μl. The incubation was followed by rapidfiltration on GF/B filters (pre-soaked with 100 μl of 0.5% PEI in Tris50 mM shaking at 200 rpm for two hours). The filtration was made using acell-harvester and the filter plates were then washed five times withice cold washing buffer containing 0.5 M NaCl. After harvesting, theplates were dried at 55° C. for 60 min, then we added scintillationfluid (Microscint 40, 40 microl in each well) and the amount ofradioactivity on the filter was determined in Packard top-counter aftershaking the plates for two hours at 200 rpm at room temperature.

Binding Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂x6H₂O pH 7.4.Washing Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂x6H₂O and 0.5 M NaClpH 7.4.

Indirect measurement of affinity of H3R inverse agonists: twelveincreasing concentrations (ranging from 10 μM to 0.3 nM) of the selectedcompounds were always tested in competition binding experiments usingmembrane of the human HR3-CHO cell line. An appropriate amount ofprotein, e.g. approximately 500 cpm binding of RAMH at Kd, wereincubated for 1 hour at room temperature in 250 μl final volume in96-well plates in presence of ³H(R)α-Methylhistamine (1 nM finalconcentration=Kd). Non-specific binding was determined using a 200 foldexcess of cold (R)α-Methylhistamine dihydrobromide.

All compounds were tested at a single concentration in duplicates.Compounds that showed an inhibition of [³H]-RAMH by more than 50% weretested again to determine IC₅₀ in a serial dilution experiment. Ki'swere calculated from IC₅₀ based on Cheng-Prusoff equation (Cheng, Y,Prusoff, W H (1973) Biochem Pharmacol 22, 3099-3108).

The compounds of the present invention exhibit K_(i) values within therange of about 1 nM to about 1000 nM, preferably of about 1 nM to about100 nM, and more preferably of about 1 nM to about 30 nM. The followingtable shows measured values for some selected compounds of the presentinvention.

K_(i) (nM) Example 5 28.7 Example 84 35.6 Example 97 13.4 Example 15025.2 Example 221 22.6 Example 245 41.0

Demonstration of additional biological activities of the compounds ofthe present invention may be accomplished through in vitro, ex vivo, andin vivo assays that are well known in the art. For example, todemonstrate the efficacy of a pharmaceutical agent for the treatment ofobesity-related disorders such as diabetes, Syndrome X, oratherosclerotic disease and related disorders such ashypertriglyceridemia and hypercholesteremia, the following assays may beused.

Method for Measuring Blood Glucose Levels

db/db mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean blood glucose levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. At this point, the animals are bled again by eye ortail vein and blood glucose levels are determined.

Method for Measuring Triglyceride Levels

hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean serum triglyceride levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. The animals are then bled again by eye or tail vein,and serum triglyceride levels are determined.

Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoAl mice are bled andgrouped with equivalent mean plasma HDL-cholesterol levels. The mice areorally dosed once daily with vehicle or test compound for 7 to 14 days,and then bled on the following day. Plasma is analyzed forHDL-cholesterol.

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable, into a galenical administration form together with suitable,non-toxic, inert, therapeutically compatible solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,preferably 0.5-100 mg, of a compound of formula I.

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 1[2-(1,1-Dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone

To the solution of 0.20 g (0.57 mmol)5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride in 2 mL N,N-dimethylformamide, 0.19 g (0.60 mmol)O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 82 mg (0.60 mmol) thiomorpholine 1,1-dioxide(commercially available) and 0.58 mL (0.44 g, 3.4 mmol)N,N-diisopropylethylamine were added. After 1 h the solution was pouredon saturated aqueous sodium bicarbonate solution, the phases wereseparated and the aqueous phase was extracted three times with ethylacetate. The combined organic layers were washed three times with waterfollowed by brine, dried over magnesium sulfate, filtered andevaporated. The residue was flash-chromatographed twice on silica gelwith dichloromethane:methanol:ammonia (12:1:0.1 v/v) as eluant to give0.13 g (64%) of the desired compound as a light brown solid.

MS (ISP): 433.3 (M+H⁺)

Intermediate 15-(4-Isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid ethylester

To the solution of 5.0 g (21.4 mmol) 1H-indole-2,5-dicarboxylic acid2-ethyl ester (prepared according to J. Org. Chem. 1953, 18, 345-57) in50 mL N,N-dimethylformamide, 8.6 g (26.8 mmol)O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available) were added. After 10 min., 3.44 g (26.8 mmol)1-isopropylpiperazine (commercially available) and 18.3 mL (13.9 g,107.4 mmol) N,N-diisopropylethylamine were added. After 45 min. thereaction mixture was poured on saturated aqueous sodium bicarbonatesolution and was extracted three times with ethyl acetate. The combinedorganic layers were washed three times with water followed by brine,dried over magnesium sulfate, filtered and evaporated. The residue wasflash-chromatographed on silica gel withdichloromethane:methanol:ammonia (9:1:0.1 v/v) and ethylacetate:methanol (9:1) as eluant to give 5.5 g (74%) of the desiredcompound as a light yellow solid.

MS (ISP): 344.3 (M+H⁺)

5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride

The solution of 2.8 g (8.1 mmol)5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid ethylester in 110 mL tetrahydrofuran, 0.24 g (10.1 mmol) lithium hydroxidewas added followed by 55 mL of water. The resulting yellow solution wasstirred under reflux for 1.75 hours. The organic solvent was evaporatedand the remaining turbid aqueous residue was treated with 4 Mhydrochloric acid until a pH of 2 was reached. The volatile componentswere to dryness to give 3 g of the desired compound as the hydrochloridesalt containing lithium chloride. This material was pure enough for thenext step without further purification.

MS (ISP): 316.1 (M+H⁺)

Intermediate 25-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester

The title compound was synthesized in analogy to example 1, intermediate1 a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 1-cyclopentylpiperazine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a light brown solid (74%).

MS (ISP): 344.3 (M+H⁺)

5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride

The title compound was synthesized in analogy to example 1, intermediate1 b), from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester, to give the desired product as a light brown solid (60%).

MS (ISP): 342.3 (M+H⁺)

Example 2[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), pyrrolidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethyl-formamide togive the desired product.

MS (TIC): 395.1 (M+H⁺)

Example 3[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 2-methyl-pyrrolidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 409.3 (M+H⁺)

Example 4[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 2-isopropylpyrrolidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 437.2 (M+H⁺)

Example 5[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-piperidin-1-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), piperidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 409.3 (M+H⁺)

Example 6[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methyl-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-methyl piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethyl-formamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 423.2 (M+H⁺)

Example 7[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-methoxy piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 439.3 (M+H⁺)

Example 8[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 2,4-difluoro piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 445.3 (M+H⁺)

Example 9[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-hydroxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 2,4-difluoro piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 425.1 (M+H⁺)

Example 10[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), morpholine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 411.2 (M+H⁺)

Example 11[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-thiomorpholin-4-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), thiomorpholine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 427.1 (M+H⁺)

Example 12[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(3-fluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 3-fluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 427.2 (M+H⁺)

Example 13[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-trifluoromethylpiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 477.1 (M+H⁺)

Example 14[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 3,4-dihydro-1H-isoquinoline(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 457.3 (M+H⁺)

Example 155-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acidbenzyl-methyl-amide

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), methylbenzylamine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 445.3 (M+H⁺)

Example 16[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-pyrrolidin-1-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), methylbenzylamine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 369.1 (M+H⁺)

Example 17[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), methylbenzylamine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 383.2 (M+H⁺)

Example 18[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 2-isopropylpyrrolidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 411.2 (M+H⁺)

Example 19[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-piperidin-1-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), piperidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 383.2 (M+H⁺)

Example 20[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methyl-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-methyl piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 397.2 (M+H⁺)

Example 21[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-methoxy piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 397.2 (M+H⁺)

Example 22(4-Hydroxy-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-hydroxy piperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 399.1 (M+H⁺)

Example 23[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), morpholine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 385.1 (M+H⁺)

Example 24[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-thiomorpholin-4-yl-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), thiomorpholine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 401.2 (M+H⁺)

Example 25(3-Fluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 3-fluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 401.2 (M+H⁺)

Example 26[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-trifluoromethylpiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 451.2 (M+H⁺)

Example 27 5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid benzylamide

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), benzylamine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 405.3 (M+H⁺)

Example 28 5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid benzyl-methyl-amide

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), methylbenzylamine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 419.2 (M+H⁺)

Example 29 5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid cyclopentylamide

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), cyclopentylamine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 383.2 (M+H⁺)

Example 30Azepan-1-yl-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), azepane (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 397.2 (M+H⁺)

Example 31Azepan-1-yl-[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), azepane (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product after purification by preparative HPLC onreversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 423.2 (M+H⁺)

Example 32(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 419.2 (M+H⁺)

Example 33(3,4-Dihydro-1H-isoquinolin-2-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 3,4-Dihydro-1H-isoquinoline(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product after purification bypreparative HPLC on reversed phase eluting with a gradient formed fromacetonitrile/water/formic acid.

MS (TIC): 431.3 (M+H⁺)

Example 34[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), thiomorpholine 1,1-dioxide(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide to give the desired product as a light yellowsolid (58%).

MS (TIC): 459.3 (M+H⁺)

Example 355-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(4-fluoro-phenyl)-amide

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 34, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 4-fluoroaniline (commercially available) andN,N-diisopropylethylamine in N,N-dimethylformamide, to give the desiredproduct as a yellow solid (43%).

MS (TIC): 435.2 (M+H⁺)

Example 365-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(4-fluoro-phenyl)-methyl-amide

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 34, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 4-fluoro-N-methylaniline (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a yellow solid (44%).

MS (TIC): 449.2 (M+H⁺)

Example 375-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(2,6-dimethyl-phenyl)-amide

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 34, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 2,6-dimethylaniline (commercially available)and N,N-diisopropylethylamine in N,N-dimethylformamide, to give thedesired product as a yellow solid (22%).

MS (TIC): 445.2 (M+H⁺)

Example 385-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(2,4,6-trimethyl-phenyl)-amide

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 34, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 2,4,6-trimethylaniline (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a light yellow solid (7%).

MS (TIC): 459.3 (M+H⁺)

Example 395-(4-Cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(2-fluoro-phenyl)-amide

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 34, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 2-fluoroaniline (commercially available) andN,N-diisopropylethylamine in N,N-dimethylformamide, to give the desiredproduct as a light yellow solid (6%).

MS (TIC): 435.2 (M+H⁺)

Example 40(4-Cyclopentyl-piperazin-1-yl)-[2-(2,3-dihydro-indole-1-carbonyl)-1H-indol-5-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 34, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), indoline (commercially available) andN,N-diisopropyl-ethylamine in N,N-dimethylformamide, to give the desiredproduct as a light yellow solid (49%).

MS (TIC): 443.1 (M+H⁺)

Example 41[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acidhydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light brownsolid (83%).

MS (TIC): 431.2 (M+H⁺)

Intermediates5-(4-Cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid ethylester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 1-cyclobutylpiperazine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a light brown solid (62%).

MS (TIC): 356.1 (M+H⁺)

5-(4-Cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from 5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, to give the desired product as a brown solid (99%).

MS (TIC): 328.1 (M+H⁺)

Examples 42 and 43(4,4-Difluoro-piperidin-1-yl)-[5-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanoneand(4,4-Difluoro-piperidin-1-yl)-[5-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compounds were obtained through separation of the enantiomersof(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(intermediate a) by chiral HPLC chromatography (Chiralpak AD column;Daicel; flow: 35 mL/min; column size: 5×55 cm; mobile phase: ethanol:2-propanol (1:4 v/v); UV detection at 220 nM). The first-elutingenantiomer was obtained as a light brown foam (29%) and the secondenantiomer was obtained as a colorless solid (42%).

MS (TIC): 405.4 (M+H⁺)—enantiomer 1

MS (TIC): 405.4 (M+H⁺)—enantiomer 2

Intermediates(RS)-(4,4-Difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from(RS)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, as a colorless solid (77%).

MS (TIC): 405.2 (M+H⁺)

(RS)-5-(3-Dimethylamino-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 3-(dimethylamino)pyrrolidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a light brown solid (68%).

MS (TIC): 330.2 (M+H⁺)

(RS)-5-(3-Dimethylamino-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid; hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from(RS)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, to give the desired product as a light brown solid(90%).

MS (TS): 302.1 (M+H⁺)

Example 44[2-(4,4-Difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light yellowsolid (74%).

MS (TIC): 445.1 (M+H⁺)

Intermediates5-((S)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light yellowfoam (90%).

MS (TIC): 370.0 (M+H⁺)

5-((S)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid; hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, to give the desired product as a light brown foam. Theso-obtained product was pure enough for the next step without furtherpurification.

MS (TS): 342.0 (M+H⁺)

Example 45[2-(4,4-Difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a colorless solid(74%).

MS (TIC): 445.1 (M+H⁺)

Intermediates5-((R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), (R)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light brown foam(69%).

MS (TIC): 370.1 (M+H⁺)

5-((R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid; hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from5-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, to give the desired product as a light brown solid(93%). The so-obtained product was pure enough for the next step withoutfurther purification.

MS (ISP): 342.0 (M+H⁺)

Example 46[5-(4-Isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone(5-Bromo-1H-indol-2-yl)-morpholin-4-yl-methanone

A mixture of 5-bromoindole-2-carboxylic acid (5 g, 21 mmol), and1,1′-carbonyldiimidazole (4.39 g, 27 mmol) in tetrahydrofuran (60 mL)was stirred at room temperature overnight. Morpholine (3.63 mL, 42 mmol)was added and the mixture was stirred for an additional 40 min. Thereaction mixture was partitioned between ethyl acetate and an aqueoussolution of sodium bicarbonate. The organic layer was washed withhydrochloric acid (1N) and brine, then dried over sodium sulfate,filtered and evaporated in vacuo, to give 6.74 g (99%) of the desiredcompound as a yellow solid which was used without further purification.

MS (TIC): 310.0 (M+H⁺)

[5-Bromo-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

To a mixture of (5-bromo-1H-indol-2-yl)-morpholin-4-yl-methanone (6.64g, 20 mmol) in tetrahydrofuran (60 mL) was added sodium hydride (60%dispersion in oil, 979 mg, 24 mmol) in several portions. The mixture wasstirred 15 min at room temperature then 2,2,2-trifluoroethyltrifluoromethanesulfonate (6.16 g, 27 mmol) was added and the reactionmixture was refluxed overnight. The reaction mixture was partitionedbetween ethyl acetate and an aqueous solution of sodium bicarbonate. Theorganic layer was washed with hydrochloric acid (1N) and brine, driedover sodium sulfate, filtered and evaporated in vacuo. The crude productwas purified by flash chromatography on silica gel withdichloromethane:ethyl acetate (98:2 to 94:6 v/v) as eluant, to give 4.65g (58%) of the desired compound as an off-white solid.

MS (TIC): 392.0 (M+H⁺)

2-(Morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid ethyl ester

A mixture of[5-bromo-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone(1.49 g, 4 mmol), palladium acetate (171 mg, 0.76 mmol), 1,3-bis(diphenylphosphino)propane (346 mg, 0.84 mmol), triethylamine (0.58 mL,4 mmol), ethanol (3 mL) and dimethylsulfoxide (3 mL) was flushed withcarbon monoxide. The reaction mixture was stirred vigorously at 75° C.(oil bath), under carbon monoxide (1 Atm) for 19 h. The red mixture wasdiluted with ethyl acetate, filtered and partitioned between ethylacetate and brine. The organic layer was washed with brine and dried invacuo. The crude product was purified by flash chromatography on silicagel with dichloromethane:ethyl acetate (98:2 v/v) as eluant, to give 924mg (63%) of the desired compound as an off-white solid.

MS (TIC): 385.5 (M+H⁺)

2-(Morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid

A solution of2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid ethyl ester (924 mg, 2.4 mmol) and lithium hydroxide monohydrate(200 mg, 4.8 mmol) in tetrahydrofuran (8 mL), methanol (2 mL) and water(4 mL) was refluxed for 3 h. The volatiles were removed in vacuo and theresidue was dissolved in water and acidified with hydrochloric acid(1N). The precipitate was filtered, washed with water and dried invacuo. The crude product was purified by flash chromatography on silicagel with dichloromethane:methanol (98:2 then 19:1 v/v) as eluant, togive 727 mg (85%) of the desired compound as an off-white solid.

MS (TIC): 355.5 (M−H⁺)

[5-(4-Isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

A mixture of2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid (100 mg, 0.28 mmol) and 1,1′-carbonyl-diimidazole (59 mg, 0.37mmol) in tetrahydrofuran was stirred at room temperature overnight.1-Isopropylpiperazine (72 mg, 0.56 mmol) was then added and the mixturewas stirred for an additional 40 min. The volatiles were removed invacuo and the residue was purified by flash chromatography on silica gelwith dichloromethane:methanol:ammonia (95:5:0.25 v/v) as eluant, to give90 mg (68%) of the desired compound as an off-white solid.

MS (TIC): 467.5 (M+H⁺)

Example 47[5-(Hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 46,intermediate e), from2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid and 1,4-diazabicyclo[4.3.0]nonane (purchased at Matrix Ref 8078),to give the desired product as a white solid (65%).

MS (ISP): 465.5 (M+H⁺)

Example 48(4-Cyclobutyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-5-yl]-methanone

The title compound was synthesized in analogy to example 46,intermediate e), from2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid and 1-cyclobutylpiperazine (commercially available), to give thedesired product as a white solid (50%).

MS (ISP): 479.5 (M+H⁺)

Example 49[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 46,intermediate e), from2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid and 1-cyclopentylpiperazine (commercially available), to give thedesired product as a white solid (49%).

MS (ISP): 493.5 (M+H⁺)

Example 50[5-(4-Cyclohexyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 46,intermediate e), from2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylicacid and 1-cyclohexylpiperazine (commercially available), to give thedesired product as a white solid (65%).

MS (ISP): 507.5 (M+H⁺)

Example 51[1-Cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The suspension of 0.15 g (0.36 mmol)(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32) and 17 mg (0.36 mmol; 55% dispersion in mineral oil) sodiumhydride in 2 mL N,N-dimethylformamide was stirred for 30 min. at 70° C.Then, 42 μL (58 mg, 0.43 mmol) cyclopropylmethyl bromide were added andthe solution was stirred another 45 min. at 70° C. After cooling to roomtemperature the reaction was poured on 10% aqueous ammonium chloridesolution and the phases were separated. The aqueous phase was extractedthree times with ethyl acetate. The combined organic layers were washedtwice with water, followed by brine, dried over magnesium sulfate,filtered and evaporated. The crude product was purified by flashchromatography on silica gel with dichloromethane:methanol:ammonia(9:1:0.1 v/v) as eluant to give 0.16 g (97%) of the desired compound asa colorless foam.

MS (TIC): 437.1 (M+H⁺)

Example 52(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a colorless oil(50%).

MS (TIC): 501.1 (M+H⁺)

Example 53(4,4-Difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a colorless oil(54%).

MS (TIC): 461.2 (M+H⁺)

Example 54[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-acetonitrile

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), sodium hydride and bromoacetonitrile inN,N-dimethylformamide, to give the desired product as a yellow oil(54%).

MS (TIC): 458.2 (M+H⁺)

Example 55[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide give the desired product as a colorless foam(44%).

MS (TIC): 500.2 (M+H⁺)

Example 56[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate inN,N-dimethylformamide, to give the desired product as a colorless foam(31%).

MS (TIC): 527.1 (M+H⁺)

Example 57[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 51, from(4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone(example 10), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(38%).

MS (TIC): 465.2 (M+H⁺)

Example 58[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 51, from(4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone(example 10), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a colorless foam(31%).

MS (TIC): 453.3 (M+H⁺)

Example 59[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), sodium hydride and 2-bromopropane in N,N-dimethylformamidegive the desired product as a colorless foam (27%).

MS (TIC): 487.2 (M+H⁺)

Example 60(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-methanesulfonyl-1-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), sodium hydride and methanesulfonyl chloride inN,N-dimethylformamide, to give the desired product as a colorless foam(34%).

MS (TIC): 497.0 (M+H⁺)

Example 61[5-(4-Cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-acetonitrile

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), sodium hydride and bromoacetonitrile inN,N-dimethylformamide, to give the desired product as a light brown foam(42%).

MS (TIC): 484.3 (M+H⁺)

Example 62[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-methanesulfonyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), sodium hydride and methanesulfonyl chloride inN,N-dimethylformamide, to give the desired product as a colorless foam(35%).

MS (TIC): 523.1 (M+H⁺)

Example 63(4-Cyclopentyl-piperazin-1-yl)-[1-methanesulfonyl-2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone(example 10), sodium hydride and bromoacetonitrile inN,N-dimethylformamide, to give the desired product as a colorless foam(55%).

MS (TIC): 450.2 (M+H⁺)

Example 64(4-Cyclopentyl-piperazin-1-yl)-[1-methanesulfonyl-2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone(example 10), sodium hydride and methanesulfonyl chloride inN,N-dimethylformamide, to give the desired product as a colorless foam(54%).

MS (TIC): 489.2 (M+H⁺)

Example 65[1-Benzyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The suspension of 0.15 g (0.36 mmol)(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 72 μL (76 mg, 0.72 mmol) benzylalcohol and 173 mg (0.72mmol) (triphenylphosphoranylidene)acetonitrile in 2 mL toluene wasstirred for 3 hours under reflux. The volatile components wereevaporated at a rotary evaporator and the residue was purified usingflash chromatography on silica gel with dichloromethane:methanol (19:1v/v) as eluant to give 0.11 g (63%) of the desired compound as a lightbrown foam.

MS (TIC): 509.5 (M+H⁺)

Example 66(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-p-tolyl-1H-indol-2-yl]-methanone

The suspension of 0.15 g (0.36 mmol)(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 146 mg (1.1 mmol) 4-methylphenylboronic acid, 0.13 g (0.72mmol) copper(II) acetate and 0.12 mL (0.11 g, 1.43 mmol) pyridine in 5mL dichloromethane was stirred for 3 days at room temperature. Thevolatile components were evaporated at a rotary evaporator and theresidue was purified using flash chromatography on silica gel withdichloromethane:methanol (19:1 v/v) as eluant to give 89 mg (49%) of thedesired compound as a colorless foam.

MS (TIC): 509.4 (M+H⁺)

Example 67(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 4-methoxyphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (41%).

MS (TIC): 525.3 (M+H⁺)

Example 68(4,4-Difluoro-piperidin-1-yl)-[1-(4-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 4-fluorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless foam(88%).

MS (TIC): 513.4 (M+H⁺)

Example 69[1-(4-Chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 4-chlorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless foam(69%).

MS (TIC): 529.3 (M+H⁺)

Example 70(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (47%).

MS (TIC): 563.4 (M+H⁺)

Example 714-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 4-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless foam(52%).

MS (TIC): 520.3 (M+H⁺)

Example 72[1-(3-Chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 3-chlorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless foam(37%).

MS (TIC): 529.2 (M+H⁺)

Example 733-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 3-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless foam(77%).

MS (TIC): 520.3 (M+H⁺)

Example 74[1-Benzyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

To the suspension of 105 mg (0.70 mmol)(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62) in 1 mL toluene, 1.39 mL (0.70mmol; 0.5M solution in toluene) potassium bis(trimethylsilyl)amide wasadded. After 10 min., 71 μL (74 mg, 0.70 mmol) benzylalcohol and 0.15 g(0.35 mmol)[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1) were added and the suspension was stirred for 1 h at refluxtemperature. After cooling to room temperature the reaction mixture wasevaporated to dryness, the residue was taken up in dichloromethane,filtered and the filtrate was evaporated. The crude product was purifiedby flash column chromatography on silica gel withdichloromethane:methanol:ammonia (19:1:0.1 v/v) as eluant to give 118 mg(65%) of the desired compound as a colorless foam.

MS (TIC): 523.2 (M+H⁺)

Example 75[1-(4-Chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-chlorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white solid (23%).

MS (TIC): 555.3 (M+H⁺)

Example 76[1-(3-Chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-chlorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white solid (76%).

MS (TIC): 555.2 (M+H⁺)

Example 77[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(4-fluoro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-fluorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a light yellow foam(82%).

MS (TIC): 539.4 (M+H⁺)

Example 78[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(3-fluoro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-fluorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white foam (78%).

MS (TIC): 539.4 (M+H⁺)

Example 79[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a whitefoam (51%).

MS (TIC): 589.4 (M+H⁺)

Example 80[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a whitefoam (73%).

MS (TIC): 589.5 (M+H⁺)

Example 81[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-p-tolyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-methylphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white foam (89%).

MS (TIC): 535.4 (M+H⁺)

Example 82[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-methylphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white foam (81%).

MS (TIC): 535.4 (M+H⁺)

Example 83[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-methoxyphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a white foam(73%).

MS (TIC): 551.2 (M+H⁺)

Example 84[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(3-methoxy-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-methoxyphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a white foam(73%).

MS (TIC): 551.2 (M+H⁺)

Example 854-[5-(4-Cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzoicacid methyl ester

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-methoxycarbonylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a white foam(67%).

MS (TIC): 579.3 (M+H⁺)

Example 863-[5-(4-Cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzoicacid ethyl ester

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-ethoxycarbonylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a white foam(69%).

MS (TIC): 593.4 (M+H⁺)

Example 87[5-(4-Cyclopentyl-piperazine-1-carbonyl)-2-(1,1-dioxo-1,l-thiomorpholine-4-carbonyl)-indol-1-yl]-acetonitrile

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), sodium hydride and bromoacetonitrile inN,N-dimethylformamide, to give the desired product as a light yellowfoam (7%).

MS (TIC): 498.2 (M+H⁺)

Example 884-[5-(4-Cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 4-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white foam (19%).

MS (TIC): 546.3 (M+H⁺)

Example 893-[5-(4-Cyclopentyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 8), 3-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a white foam (39%).

MS (TIC): 546.3 (M+H⁺)

Example 90(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 3-methylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a white foam(45%).

MS (TIC): 509.4 (M+H⁺)

Example 91(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a whitefoam (33%).

MS (TIC): 563.5 (M+H⁺)

Example 923-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzoicacid ethyl ester

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 3-ethoxycarbonylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightyellow foam (29%).

MS (TIC): 567.4 (M+H⁺)

Example 934-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzoicacid methyl ester

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 4-methoxycarbonylphenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (40%).

MS (TIC): 553.3 (M+H⁺)

Example 94(4,4-Difluoro-piperidin-1-yl)-[1-(4-fluoro-benzyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 74, from(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, 4-fluorobenzylalcohol and(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32) in toluene to give the compound as a colorless foam (37%).

MS (TIC): 527.1 (M+H⁺)

Example 95(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-phenyl-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 74, from(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, 1-phenylethanol and(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32) in toluene to give the compound as a light brown foam(37%).

MS (TIC): 523.3 (M+H⁺)

Example 96Cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid (3-fluoro-oxetan-3-ylmethyl)-amide

The title compound was synthesized in analogy to example 51, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(3-fluoro-oxetan-3-ylmethyl)-amide, sodium hydride and cyclopropylmethylbromide in N,N-dimethylformamide, to give the desired product as acolorless foam (40%).

MS (TIC): 457.3 (M+H⁺)

Intermediate5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid(3-fluoro-oxetan-3-ylmethyl)-amide

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochloride (example 1, intermediate b),(3-fluoro-oxetan-3-yl)-methylamine (commercially available),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a colorless solid(42%).

MS (TIC): 403.3 (M+H⁺)

Example 97[1-(3-Chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 3-chlorphenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a light brown solid(21%).

MS (TIC): 543.2 (M+H⁺)

Example 983-[2-(1,1-Dioxo-thiomorpholine-4-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 3-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless solid(16%).

MS (TIC): 534.3 (M+H⁺)

Example 99(1,1-Dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightyellow foam (35%).

MS (TIC): 577.1 (M+H⁺)

Example 100[1-(4-Chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 4-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlesssolid (34%).

MS (TIC): 569.3 (M+H⁺)

Example 101[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a light yellowfoam (33%).

MS (TIC): 501.2 (M+H⁺)

Example 102[1-(3-Chloro-phenyl)-5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightyellow solid (20%).

MS (TIC): 569.3 (M+H⁺)

Example 103[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(4-fluoro-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 4-fluorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightyellow solid (34%).

MS (TIC): 553.2 (M+H⁺)

Example 104[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(3-fluoro-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 3-fluorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightyellow solid (46%).

MS (TIC): 553.2 (M+H⁺)

Example 105[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightyellow solid (15%).

MS (TIC): 603.2 (M+H⁺)

Example 106[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightyellow solid (40%).

MS (TIC): 603.2 (M+H⁺)

Example 107[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-p-tolyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 4-methylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightyellow solid (69%).

MS (TIC): 549.3 (M+H⁺)

Example 108[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), 3-methylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightyellow solid (76%).

MS (TIC): 549.3 (M+H⁺)

Example 109[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a light yellowsolid (70%).

MS (TIC): 513.3 (M+H⁺)

Example 110[5-(4-Cyclopentyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone(example 34), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a light yellowsolid (60%).

MS (TIC): 541.2 (M+H⁺)

Example 111[1-(4-Chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 4-chlorophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless solid(34%).

MS (ISP): 543.3 (M+H⁺)

Example 1124-[2-(1,1-Dioxo-thiomorpholine-4-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 4-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a light brown solid(11%).

MS (ISP): 534.3 (M+H⁺)

Example 113(1,1-Dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightbrown solid (12%).

MS (ISP): 577.2 (M+H⁺)

Example 114[1-Cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(27%).

MS (TIC): 487.2 (M+H⁺)

Example 115(1,1-Dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate inN,N-dimethylformamide, to give the desired product as a colorless foam(74%).

MS (TIC): 515.2 (M+H⁺)

Example 116[5-(4-Isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

A mixture of 0.15 g (0.039 mmol)[5-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone,0.1 g (0.039 mmol) 3-iodobenzotrifluoride, 0.006 g (0.00052 mmol)trans-1,2-diaminocyclohexane, 0.003 g (0.00016 mmol) copper(I)iodide and0.174 g (0.081 mmol) potassium phosphate in 1 mL dioxane was heated toreflux for 43 h. After 20 h another 0.006 g (0.00052 mmol)trans-1,2-diaminocyclohexane and 0.003 g (0.00016 mmol) copper(I)iodidewas added. After filtration the mixture was evaporated to dryness andthe residue was purified on silica eluting with a gradient formed fromCH₂Cl₂, methanol and 2N NH₃. The product fractions were evaporated toyield 0.147 g (71%) of the title compound as brown foam.

MS (TIC): 529.1 (M+H⁺).

Example 117[5-(4-Isopropyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to example 116, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanoneand 4-iodobenzotrifluoride.

MS (TIC): 529.1 (M+H⁺).

Example 1184-[5-(4-Isopropyl-piperazine-1-carbonyl)-2-(morpholine-4-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 116, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanoneand 4-iodobenzonitrile.

MS (TIC): 486.3 (M+H⁺).

Example 119(4,4-Difluoro-piperidin-1-yl)-[1-(3-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 3-fluorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a yellow oil(35%).

MS (TIC): 513.3 (M+H⁺)

Example 120(1,1-Dioxo-1,l,6-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-phenyl-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 74, from(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, 1-phenylethanol in toluene, to give thedesired product as a light brown solid (23%).

MS (TIC): 537.3 (M+H⁺)

Example 121(4,4-Difluoro-piperidin-1-yl)-[1-[1-(2-fluoro-phenyl)-ethyl]-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 74, from(cyanomethyl)-trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, 1-(2-fluorophenyl)ethanol and(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32) in toluene, to give the desired product as a light brownfoam (15%).

MS (TIC): 541.2 (M+H⁺)

Example 122[1-Cyclobutylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), sodium hydride and (bromomethyl)cyclobutane inN,N-dimethylformamide, to give the desired product as a colorless foam(69%).

MS (TIC): 487.2 (M+H⁺)

Examples 123 and 124(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-((R)-1-phenyl-ethyl)-1H-indol-2-yl]-methanoneand(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-((S)-1-phenyl-ethyl)-1H-indol-2-yl]-methanone

The title compounds were obtained through separation of the enantiomersof(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-phenyl-ethyl)-1H-indol-2-yl]-methanoneby chiral HPLC chromatography (Chiralpak AD column; Daicel; flow: 35mL/min; column size: 5×55 cm; mobile phase: n-heptane: 2-propanol (30:70v/v); UV detection at 220 nM). The first-eluting enantiomer was obtainedas a light brown foam (31%) and the second enantiomer was obtained as alight brown foam (37%).

MS (TIC): 405.4 (M+H⁺)—enantiomer 1

MS (TIC): 405.4 (M+H⁺)—enantiomer 2

Example 123 was independently synthesized according to example 74 underinversion of the configuration (e.e. >94%), from(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, (S)-1-phenylethanol and(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32) in toluene, to give the compound as a light brown foam(32%).

MS (TIC): 523.2 (M+H⁺)

Intermediate(RS)-(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-phenyl-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 74, from(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, 1-phenylethanol and(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32) in toluene, to give the compound as a light brown foam(37%).

MS (TIC): 523.2 (M+H⁺)

Example 125[1-(3-Chloro-phenyl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlesssolid (10%).

MS (ISP): 541.3 (M+H⁺)

Example 1263-[5-(4-Cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 3-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a colorless foam(20%).

MS (ISP): 532.2 (M+H⁺)

Example 127[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightbrown foam (60%).

MS (TIC): 575.3 (M+H⁺)

Example 128[1-(4-Chloro-phenyl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 4-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (56%).

MS (TIC): 541.2 (M+H⁺)

Example 1294-[5-(4-Cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 4-cyanophenylboronic acid, copper(II) acetate and pyridinein dichloromethane, to give the desired product as a off-white foam(30%).

MS (ISP): 532.2 (M+H⁺)

Example 130[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (49%).

MS (TIC): 575.3 (M+H⁺)

Example 131[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(73%).

MS (TIC): 485.3 (M+H⁺)

Example 132[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a colorlessfoam (50%).

MS (TIC): 513.2 (M+H⁺)

Example 133[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a colorless foam(34%).

MS (TIC): 473.1 (M+H⁺)

Example 134[1-Cyclopropylmethyl-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 42, intermediate a)), sodium hydride and cyclopropylmethylbromide in N,N-dimethylformamide, to give the desired product as acolorless foam (53%).

MS (TIC): 459.3 (M+H⁺)

Example 135(RS)-(4,4-Difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 42, intermediate a)), sodium hydride and 2,2,2-trifluoroethylmethanesulfonate in N,N-dimethylformamide, to give the desired productas a colorless foam (73%).

MS (TIC): 487.1 (M+H⁺)

Example 136(RS)-(4,4-Difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 42, intermediate a)), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a colorless foam(35%).

MS (TIC): 447.1 (M+H⁺)

Example 137(RS)-[1-(3-Chloro-phenyl)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 42, intermediate a)), 3-chlorophenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asa colorless foam (30%).

MS (ISP): 515.4 (M+H⁺)

Example 138(RS)-3-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 42, intermediate a)), 3-cyanophenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asa colorless foam (40%).

MS (ISP): 506.3 (M+H⁺)

Example 139(RS)-(4,4-Difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 42, intermediate a)), 3-(trifluoromethyl)phenylboronic acid,copper(II) acetate and pyridine in dichloromethane, to give the desiredproduct as a light brown foam (60%).

MS (ISP): 549.5 (M+H⁺)

Example 140[1-(3-Chloro-phenyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone,3-chlorophenylboronic acid, copper(II) acetate and pyridine indichloromethane, to give the desired product as an off-white foam (28%).

MS (ISP): 529.3 (M+H⁺)

Intermediates(4,4-Difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidhydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4-fluoroaniline(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light yellowfoam (72%).

MS (TIC): 419.2 (M+H⁺)

5-(4-Dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid;1:1 hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester, to give the desired product as a light brown solid. Theso-obtained product was pure enough without further purification for thenext step.

MS (TIC): 316.0 (M+H⁺)

5-(4-Dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 4-dimethylamino-piperidine dihydrochloride(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light yellowfoam (67%).

MS (TIC): 344.1 (M+H⁺)

Example 1413-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 140, intermediate a)), 3-cyanophenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asan off-white foam (26%).

MS (ISP): 520.3 (M+H⁺)

Example 142(4,4-Difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 140, intermediate a)), 3-(trifluoromethyl)phenylboronic acid,copper(II) acetate and pyridine in dichloromethane, to give the desiredproduct as a light brown foam (48%).

MS (ISP): 563.4 (M+H⁺)

Example 143[1-(4-Chloro-phenyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methane

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 140, intermediate a)), 4-chlorophenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asa light brown foam (57%).

MS (ISP): 529.3 (M+H⁺)

Example 1444-[2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(4-dimethylamino-piperidine-1-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 140, intermediate a)), 4-cyanophenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asan off-white foam (22%).

MS (TIC): 520.3 (M+H⁺)

Example 145(4,4-Difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 140, intermediate a)), 4-(trifluoromethyl)phenylboronic acid,copper(II) acetate and pyridine in dichloromethane, to give the desiredproduct as a colorless foam (20%).

MS (TIC): 563.4 (M+H⁺)

Example 146[1-Cyclopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), cyclopropylboronic acid (commercially available),copper(II) acetate and pyridine using chloroform as solvent and stirringat 50° C. for 4 days, to give the desired product as a light brown foam(12%).

MS (TIC): 459.3 (M+H⁺)

Example 147(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(1-methyl-1-phenyl-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 74, from(cyanomethyl)trimethylphosphonium chloride (prepared according toTetrahedron Lett. 1996, 37 (14), 2459-62), potassiumbis(trimethylsilyl)amide, 2-phenyl-2-propanol and(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), to give the desired product as a yellow foam (9%).

MS (TIC): 537.5 (M+H⁺)

Example 148[1-Cyclopropylmethyl-5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone,(example 140, intermediate a)), sodium hydride and cyclopropylmethylbromide in N,N-dimethylformamide, to give the desired product as a lightyellow oil (36%).

MS (TIC): 473.3 (M+H⁺)

Example 149(4,4-Difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone,(example 140, intermediate a)), sodium hydride and 2,2,2-trifluoroethylmethanesulfonate in N,N-dimethylformamide, to give the desired productas a light yellow foam (63%).

MS (TIC): 501.2 (M+H⁺)

Example 150[1-Cyclobutyl-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), cyclobutylboronic acid (commercially available),copper(II) acetate and pyridine using chloroform as solvent and stirringunder reflux for 6 days, to give the desired product as a light brownfoam (14%).

MS (TIC): 473.1 (M+H⁺)

Example 151[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(4-methanesulfonyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 4-(methanesulphonyl)benzeneboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asa light brown solid (12%).

MS (TIC): 585.2 (M+H⁺)

Example 152[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(3,5-difluoro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 3,5-difluorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (69%).

MS (TIC): 543.3 (M+H⁺)

Example 153[1-(2-Chloro-pyridin-4-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 2-chloropyridine-4-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a off-whitefoam (10%).

MS (TIC): 542.2 (M+H⁺)

Example 154[1-(6-Chloro-pyridin-3-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 2-chloropyridine-5-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a off-whitefoam (26%).

MS (TIC): 542.2 (M+H⁺)

Example 155[1-Benzo[1,3]dioxol-5-yl-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 3,4-methylenedioxybenzeneboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (24%).

MS (TIC): 551.1 (M+H⁺)

Example 156[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(4-morpholin-4-yl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 4-morpholinophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightbrown foam (31%).

MS (TIC): 592.3 (M+H⁺)

Example 157[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(6-morpholin-4-yl-pyridin-3-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 2-morpholino-5-pyridineboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightbrown foam (29%).

MS (TIC): 593.4 (M+H⁺)

Example 158[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(2-methoxy-pyrimidin-5-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 2-methoxypyrimidine-5-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as an off-whitefoam (11%).

MS (TIC): 539.4 (M+H⁺)

Example 159(4,4-Difluoro-piperidin-1-yl)-[5-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 42), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a white foam(85%).

MS (TIC): 527.1 (M+H⁺)

Example 160(4,4-Difluoro-piperidin-1-yl)-[5-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 43), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a white foam(85%).

MS (TIC): 527.1 (M+H⁺)

Example 161N-{4-[5-(4-Cyclobutyl-piperazine-1-carbonyl)-2-(4,4-difluoro-piperidine-1-carbonyl)-indol-1-yl]-phenyl}-methanesulfonamide

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 41), 4-(methanesulfonylamino)phenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asa colorless foam (19%).

MS (TIC): 598.2 (M+H⁺)

Example 162[1-Cyclopropylmethyl-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 44), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(80%).

MS (TIC): 499.2 (M+H⁺)

Example 163(4,4-Difluoro-piperidin-1-yl)-[1-isopropyl-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 44), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a colorless foam(45%).

MS (TIC): 487.2 (M+H⁺)

Example 162(4,4-Difluoro-piperidin-1-yl)-[5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 44), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a white foam(85%).

MS (TIC): 527.1 (M+H⁺)

Example 165(4,4-Difluoro-piperidin-1-yl)-[1-(2-methoxy-ethyl)-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 44), sodium hydride and 2-bromoethyl methyl ether inN,N-dimethylformamide, to give the desired product as a white foam(69%).

MS (TIC): 503.2 (M+H⁺)

Example 166[1-Cyclobutylmethyl-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 44), sodium hydride and (bromomethyl)cyclobutan inN,N-dimethylformamide, to give the desired product as a white foam(73%).

MS (TIC): 513.3 (M+H⁺)

Example 167(4,4-Difluoro-piperidin-1-yl)-[1-(2-hydroxy-ethyl)-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone

The solution of 90 mg (0.15 mmol)[1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanonein 3 mL dichloromethane was cooled to 0° C. and 1.0 mL (1.49 g, 13.1mmol) trifluoroacetic acid were added. The cooling bath was removed andafter stirring for 1 h at room temperature the pH of the solution wasneutralized by adding 1M aqueous sodium hydroxide solution. The phaseswere separated and the aqueous phase was extracted three times withdichloromethane. The combined organic layers were dried over magnesiumsulfate, filtered and evaporated. The crude product was purified byflash column chromatography on silica gel with dichloromethane:methanolas eluant (gradient 100:0 to 50:50) to give 41 mg (56%) of the desiredcompound as a white foam.

MS (TIC): 489.3 (M+H⁺)

Intermediate[1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(example 44), sodium hydride and(2-bromoethoxy)-tert-butyldimethylsilane (commercially available) inN,N-dimethylformamide, to give the desired product as a colorless oil(44%).

MS (TIC): 603.3 (M+H⁺)

Example 168[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropyl-ethylamine inN,N-dimethylformamide, to give the desired product as a light yellowsolid (44%).

MS (TIC): 458.2 (M+H⁺)

Intermediates 5-([1,4′]Bipiperidinyl-1′-carbonyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 4-piperidinopiperidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a brown solid (67%).

MS (ISP): 370.1 (M+H⁺)

5-([1,4′]Bipiperidinyl-1′-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from 5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indole-2-carboxylic acidethyl ester, to give the desired product as a brown solid (>100%). Theso-obtained product was pure enough for the next step without furtherpurification.

MS (ISP): 354.3 (M−H)

Example 169(4,4-Difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a yellow solid(67%).

MS (ISP): 445.1 (M+H⁺)

Intermediates5-(4-Pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 4-(1-pyrrolidinyl)-piperidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a brown solid (67%).

MS (ISP): 370.1 (M+H⁺)

5-(4-Pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester, to give the desired product as a brown solid (>100%). Theso-obtained product was pure enough for the next step without furtherpurification.

MS (ISP): 342.0 (M−H)

Example 170[2-(4,4-Difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (commercially available), 4,4-difluoropiperidine(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a brown solid(86%).

MS (ISP): 461.1 (M+H⁺)

Intermediates5-(4-Morpholin-4-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester

The title compound was synthesized in analogy to example 1, intermediatea), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 4-(piperidin-4-yl)-morpholine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a light yellow foam (72%).

MS (ISP): 386.2 (M+H⁺)

5-(4-Morpholin-4-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid;hydrochloride

The title compound was synthesized in analogy to example 1, intermediateb), from5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indole-2-carboxylic acidethyl ester, to give the desired product as a brown solid (>100%). Theso-obtained product was pure enough for the next step without furtherpurification.

a anti-hypertensive agent.

Example 171[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless solid(91%).

MS (ISP): 513.4 (M+H⁺)

Example 172[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide to give the desired product as a colorlesssolid (89%).

MS (ISP): 541.2 (M+H⁺)

Example 173[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1-isopropyl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a brown oil (62%).

MS (ISP): 501.4 (M+H⁺)

Example 174[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1-(2-chloro-pyridin-4-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), 2-chloropyridine-4-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a yellowsolid (35%).

MS (ISP): 570.3 (M+H⁺)

Example 175[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1-(3-chloro-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a light redsolid (77%).

MS (ISP): 569.4 (M+H⁺)

Example 176[5-([1,4′]Bipiperidinyl-1′-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a brownoil (66%).

MS (ISP): 603.2 (M+H⁺)

Example 177[5-([1,4]Bipiperidinyl-1′-carbonyl)-1-(6-chloro-pyridin-3-yl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone(example 168), 2-chloropyridine-5-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a brown oil(57%).

MS (ISP): 570.3 (M+H⁺)

Example 178[1-Cyclopropylmethyl-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a yellow solid(53%).

MS (ISP): 499.3 (M+H⁺)

Example 179(4,4-Difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide to give the desired product as a yellow solid(46%).

MS (ISP): 527.2 (M+H⁺)

Example 180(4,4-Difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a white solid(66%).

MS (ISP): 487.5 (M+H⁺)

Example 181[1-(2-Chloro-pyridin-4-yl)-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), 2-chloropyridine-4-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a yellow oil(17%).

MS (ISP): 556.1 (M+H⁺)

Example 182[1-(3-Chloro-phenyl)-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a brown oil(93%).

Example 183(4,4-Difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a brownoil (53%).

MS (ISP): 589.4 (M+H⁺)

Example 184[1-(6-Chloro-pyridin-3-yl)-5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone(example 169), 2-chloropyridine-5-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a brown oil(57%).

MS (ISP): 556.1 (M+H⁺)

Example 185[1-Cyclopropylmethyl-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone(example 170), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a white solid(16%).

MS (ISP): 515.4 (M+H⁺)

Example 186(4,4-Difluoro-piperidin-1-yl)-[5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone(example 170), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a brown oil(56%).

MS (ISP): 543.3 (M+H⁺)

Example 187(4,4-Difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone(example 170), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a brown oil (88%).

MS (ISP): 503.4 (M+H⁺)

Example 188[1-(3-Chloro-phenyl)-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone(example 170), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a whitesolid (64%).

MS (ISP): 571.3 (M+H⁺)

Example 189(4,4-Difluoro-piperidin-1-yl)-[5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone(example 170), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a brownoil (60%).

MS (ISP): 605.2 (M+H⁺)

Example 190[1-(6-Chloro-pyridin-3-yl)-5-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone(example 170), 2-chloropyridine-5-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a yellowsolid (31%).

MS (TS): 572.3 (M+H⁺)

Example 191[1-Cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone(example 21), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(62%).

MS (ISP): 467.4 (M+H⁺)

Example 192[5-(4-Isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone(example 21), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a light brownfoam (83%).

MS (ISP): 495.4 (M+H⁺)

Example 193[1-(3-Chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone(example 21), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (43%).

MS (ISP): 523.3 (M+H⁺)

Example 194[5-(4-Isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone(example 21), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (65%).

MS (ISP): 557.4 (M+H⁺)

Example 195[1-(2-Chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone(example 21), 2-chloropyridine-4-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightbrown foam (33%).

MS (ISP): 524.3 (M+H⁺)

Example 196(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 1, from5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1hydrochlorid (example 1, intermediate b),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 1,4-dioxa-8-azaspiro[4.5]decane (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired product as a light brown solid (64%).

MS (ISP): 441.2 (M+H⁺)

Example 197[1-Cyclopropylmethyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone

The title compound was synthesized in analogy to example 51, from(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 196), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(76%).

MS (ISP): 495.4 (M+H⁺)

Example 198(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 196), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a colorlessfoam (78%).

MS (ISP): 523.4 (M+H⁺)

Example 199[1-(3-Chloro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone

The title compound was synthesized in analogy to example 66, from(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 196), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightbrown foam (50%).

MS (ISP): 551.2 (M+H⁺)

Example 200(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 196), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (55%).

MS (ISP): 585.2 (M+H⁺)

Example 201[1-(2-Chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone

The title compound was synthesized in analogy to example 66, from(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 196), 2-chloropyridine-4-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a lightbrown foam (42%).

MS (ISP): 552.3 (M+H⁺)

Example 202[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 1, from5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acidhydrochloride (example 41, intermediate b)),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide, to give the desired product as a light brownsolid (82%).

MS (ISP): 445.2 (M+H⁺)

Example 203[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-cyclopropylmethyl-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), sodium hydride and cyclopropylmethyl bromide inN,N-dimethylformamide, to give the desired product as a colorless foam(80%).

MS (ISP): 499.2 (M+H⁺)

Example 204[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), sodium hydride and 2,2,2-trifluoroethyl methanesulfonatein N,N-dimethylformamide, to give the desired product as a yellow solid(73%).

MS (ISP): 527.1 (M+H⁺)

Example 205[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a light brown foam(49%).

MS (ISP): 487.2 (M+H⁺)

Example 206[5-(4-Cyclobutyl-piperazine-1-carbonyl)-2-(1,1-dioxothiomorpholine-4-carbonyl)-indol-1-yl]-acetonitrile

The title compound was synthesized in analogy to example 51, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), sodium hydride and bromoacetonitrile inN,N-dimethylformamide, to give the desired product as a yellow gum (7%).

MS (ISP): 484.3 (M+H⁺)

Example 207[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(3-fluoro-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-fluorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlesssolid (35%).

MS (ISP): 539.4 (M+H⁺)

Example 208[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-methylphenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (56%).

MS (ISP): 535.4 (M+H⁺)

Example 209[1-(3-Chloro-phenyl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-chlorophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (72%).

MS (ISP): 555.2 (M+H⁺)

Example 210[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (60%).

MS (ISP): 589.5 (M+H⁺)

Example 2113-[5-(4-Cyclobutyl-piperazine-1-carbonyl)-2-(1,1-dioxothiomorpholine-4-carbonyl)-indol-1-yl]-benzonitrile

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-cyanophenylboronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (49%).

MS (ISP): 546.3 (M+H⁺)

Example 212[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(3-methanesulfonyl-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-methylsulfonylphenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as acolorless foam (37%).

MS (ISP): 599.3 (M+H⁺)

Example 213[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(3-trifluoromethoxy-phenyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 3-(trifluoromethoxy)phenylboronic acid, copper(II)acetate and pyridine in dichloromethane, to give the desired product asa light brown foam (61%).

MS (ISP): 605.2 (M+H⁺)

Example 214[1-(2-Chloro-pyridin-4-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 2-chloropyridine-4-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (32%).

MS (ISP): 556.1 (M+H⁺)

Example 215[1-(6-Chloro-pyridin-3-yl)-5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 2-chloropyridine-5-boronic acid, copper(II) acetate andpyridine in dichloromethane, to give the desired product as a colorlessfoam (54%).

MS (ISP): 556.1 (M+H⁺)

Example 216[5-(4-Cyclobutyl-piperazine-1-carbonyl)-1-(4-methanesulfonyl-phenyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone(example 202), 4-methylsulfonylphenylboronic acid, copper(II) acetateand pyridine in dichloromethane, to give the desired product as a lightbrown solid (41%).

MS (ISP): 599.3 (M+H⁺)

Example 217(1,1-Dioxothiomorpholin-4-yl)-[1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 51, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), sodium hydride and 2-bromopropane in N,N-dimethylformamide,to give the desired product as a light brown foam (42%).

MS (ISP): 475.1 (M+H⁺)

Example 218[2-(1,1-Dioxothiomorpholine-4-carbonyl)-5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-acetonitrile

The title compound was synthesized in analogy to example 51, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), sodium hydride and bromoacetonitrile inN,N-dimethylformamide, to give the desired product as a brown gum (11%).

MS (ISP): 472.0 (M+H⁺)

Example 219(1,1-Dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-m-tolyl-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 3-methylphenylboronic acid, copper(II) acetate, pyridineand using chloroforme instead of dichloromethane as solvent, to give thedesired product as a colorless foam (94%).

MS (ISP): 523.3 (M+H⁺)

Example 220(1,1-Dioxothiomorpholin-4-yl)-[1-(3-fluoro-phenyl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 3-fluorophenylboronic acid, copper(II) acetate, pyridineand using chloroforme instead of dichloromethane as solvent, to give thedesired product as a colorless foam (35%).

MS (ISP): 527.2 (M+H⁺)

Example 221(1,1-Dioxothiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(4-methanesulfonyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 4-methylsulfonylphenylboronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a colorless solid (25%).

MS (ISP): 587.4 (M+H⁺)

Example 222[1-(2-Chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 2-chloropyridine-4-boronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a light brown solid (10%).

MS (ISP): 544.3 (M+H⁺)

Example 223[1-(6-Chloro-pyridin-3-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 2-chloropyridine-5-boronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a light brown solid (19%).

MS (ISP): 544.3 (M+H⁺)

Example 224(1,1-Dioxothiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-(3-methanesulfonyl-phenyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), 3-methylsulfonylphenylboronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a colorless solid (16%).

MS (ISP): 587.4 (M+H⁺)

Example 225(1,1-Dioxothiomorpholin-4-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1-pyrimidin-5-yl-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to example 66, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), pyrimidine-5-boronic acid, copper(II) acetate, pyridine andusing chloroforme instead of dichloromethane as solvent, to give thedesired product as a colorless solid (8%).

MS (ISP): 511.3 (M+H⁺)

Example 226[1-(2-Chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone(example 32), 2-chloropyridine-4-boronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a light yellow foam (20%).

MS (ISP): 530.2 (M+H⁺)

Examples 227 and 228[4-Chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand[6-Chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone

The title compounds were synthesized in analogy to example 1, from4-chloro- or6-chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid; hydrochloride (intermediates c),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 2,4-difluoro piperidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide, togive the desired products as colorless solids in 66% (4-chloro) and 75%(6-chloro) yield.

MS (ISP): 453.3 (M+H⁺) both isomers

Intermediates2-Chloro-4-{N′-[1-ethoxycarbonyl-eth-(E/Z)-ylidene]-hydrazino}-benzoicacid

To the suspension of 1.1 g (4.93 mmol) 2-chloro-4-hydrazino-benzoic acidhydrochloride in 11 mL ethanol, 0.84 mL (0.637 g, 4.93 mmol)N,N-diisopropyl-ethylamine and 0.66 mL (0.687 g, 5.92 mmol) ethylpyruvate were added and the turbid solution was stirred under reflux for2.75 hrs. After cooling down to room temperature, the suspension wasfiltered and the filter cake was washed with ethanol to give a firstbatch of the desired product (light brown solid; 31%). The mother liquorwas kept overnight in a refrigerator and the resulting suspension wasfiltered again to give a second batch of compound (light brown solid;13%).

MS (ISP): 283.2 (M+H⁺)

4-Chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester and6-chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester

The mixture of 7.85 g (27.6 mmol)2-chloro-4-{N′-[1-ethoxycarbonyl-eth-(E/Z)-ylidene]-hydrazino}-benzoicacid and 52.6 g (0.386 mol) zinc chloride was heated under stirring to180° C. After 10 min. the heating bath was removed and 125 mL water and4.64 mL concentrated hydrochloric acid were added. The reaction mixturewas homogenized in an ultrasonic bath and then refluxed for 1 h. Theresulting homogenous suspension was put in a refrigerator for 16 hrs,filtered, washed with water and dried to give 5 g of a light brown solidcontaining a mixture of both 4-chloro- and6-chloro-1H-indole-2,5-dicarboxylic acid 2-ethyl ester (MS (ISP): 222.2(M−H⁺)).

This mixture was dissolved in 50 mL N,N-dimethylformamide and 7.5 g(23.3 mmol) O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate were added. After 10 min., 2.99 g (23.3 mmol)1-isopropylpiperazine (commercially available) was added, the solutionwas cooled to 0° C. and 15.9 mL (12.1 g, 93.6 mmol)N,N-diisopropylethylamine were added. The cooling bath was removed andafter stirring for 1.25 hrs at room temperature, the reaction solutionwas poured on 300 mL saturated aqueous sodium bicarbonate solution andextracted three times with ethyl acetate. The combined organic layerswere washed with three times with water followed by brine, dried overmagnesium sulfate, filtered and evaporated. The residue waschromatographed on silica gel with dichloromethane:methanol (1:1 v/v) aseluant and both compounds were individually purified by silica gelcolumn chromatography using isopropyl acetate:methanol (9:1 v/v) aseluant to give 175 mg (2.5%; light brown solid) of the 4-chloro and 229mg (3.2%, off-white solid) of the6-chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, respectively.

MS (ISP): 378.2 (M+H⁺). 4-Chloro isomer

MS (ISP): 378.4 (M+H⁺). 6-Chloro isomer

4-Chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid; hydrochloride and6-chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid; hydrochloride

The title compounds were synthesized in analogy to example 1,intermediate b), from 4- or6-chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, to give the title compounds as brown (4-chloro isomer)or colorless solids (6-chloro isomer) in quantitative yields. Thecompounds were pure enough for the next step without furtherpurification.

MS (ISP): 350.3 (M+H⁺). 4-Chloro isomer

MS (ISP): 350.3 (M+H⁺). 6-Chloro isomer

Example 229[6-Chloro-1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[6-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 227), 2-chloropyridine-4-boronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a colorless foam (19%).

MS (ISP): 564.4 (M+H⁺)

Example 230[4-Chloro-1-(2-chloro-pyridin-4-yl)-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 66, from[4-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 228), 2-chloropyridine-4-boronic acid, copper(II) acetate,pyridine and using chloroforme instead of dichloromethane as solvent, togive the desired product as a colorless foam (34%).

MS (ISP): 564.4 (M+H⁺)

Example 231[6-Chloro-1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1), sodium hydride and 2-bromopropane in N,N-dimethylformamide,to give the desired product as a colorless foam (61%).

MS (ISP): 495.3 (M+H⁺)

Examples 232 and 233[7-Chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand[7-Chloro-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone

The title compounds were synthesized in analogy to example 1, from7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carboxylicacid hydrochloride and 7-chloro-1H-indole-2,5-dicarboxylic acid(intermediate c), 1-isopropylpiperazine (commercially available),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available) and N,N-diisopropylethylamine inN,N-dimethylformamide. The products were separated by silica gelchromatography using dichloromethane:methanol (19:1 v/v) as eluant.

MS (ISP): 453.2 (M+H⁺)

MS (ISP): 460.3 (M+H⁺)

Intermediates(5-Bromo-7-chloro-1H-indol-2-yl)-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 1 from5-bromo-7-chloro-1H-indole-2-carboxylic acid (commercially available),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(commercially available), 2,4-difluoro piperidine (commerciallyavailable) and N,N-diisopropylethylamine in N,N-dimethylformamide togive the desired product as a colorless foam (89%).

MS (EI): 378.0 (M)

7-Chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carboxylicacid methyl ester

The mixture consistent of 100 mg (0.265 mmol)(5-bromo-7-chloro-1H-indol-2-yl)-(4,4-difluoro-piperidin-1-yl)-methanone,15 mg (0.0184 mmol) 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride and 55.6 μL (0.398 mmol) triethylamine in 1 mL ethanol and 1mL ethyl acetate was stirred overnight at 100° C. under an atmosphere ofcarbon monoxide (120 bar). After cooling to room temperature thereaction mixture is filtered, evaporated and chromatographed on silicagel with ethyl acetate:n-heptane (1:2 v/v) as eluant to give the desiredcompound as a colorless solid (69%).

MS (TIC): 713.1 (2M+H⁺); 357.1 (M+H⁺)

7-Chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carboxylicacid; hydrochloride and 7-chloro-1H-indole-2,5-dicarboxylic acid

To the solution of 0.2 g (0.56 mmol)7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carboxylicacid methyl ester in 8 mL tetrahydrofuran, 17 mg (0.71 mmol) lithiumhydroxide were added and after the addition of 4 mL water, the solutionwas stirred at reflux temperature. After eight hours, the oil bath wasremoved and the solvent was removed at a rotary evaporator. The pH ofthe residual solution was adjusted to 1-2 using 4M hydrochloric acidupon which a suspension formed. The suspension was filtered and theremaining solid was washed with a small amount of water to give amixture of the title compound and 7-chloro-1H-indole-2,5-dicarboxylicacid (60% overall) in form of a colorless solid.

MS (ISP): 341.1 (M−H⁺)

Example 234[7-Chloro-1-isopropyl-5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was synthesized in analogy to example 51, from[7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 232), sodium hydride and 2-bromopropane inN,N-dimethylformamide, to give the desired product as a colorless foam(24%).

MS (ISP): 495.2 (M+H⁺)

Example 235[5-(3-Dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to Example 1, from5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid,morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, to afford the product as an off-white solid (37%).

MS (m/z): 385.3 (M+H⁺)

Intermediates Ethyl5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylate

The title compound was synthesized in analogy to Example 1, Intermediate1a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester,3-dimethylamino-piperidine and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as a light-brown solid (63%).

MS (m/z): 343.4 (M+H)⁺

5-(3-Dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid

The title compound was synthesized in analogy to Example 1, Intermediate1b), from ethyl5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylate, toafford the product as a light-brown solid.

MS (m/z): 316.1 (M+H)⁺

Example 236[5-(3-Dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to Example 1, from5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, to afford the product as a colorless foam (42%).

MS (m/z): 427.4 (M+H⁺)

Intermediates5-(3-Dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid ethyl ester

To a solution of ethyl5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylate (1.51g, 4 mmol) in acetonitrile (30 ml) were added isopropylmethane-sulfonate(1.8 eq, 1.1 g) and caesium carbonate (1.8 eq, 2.6 g). The mixture washeated overnight at reflux. The solvent was evaporated under reducedpressure and the residue partitioned between water and tert-butylmethylether. The phases were separated, the aqueous phase extracted withtert-butylmethyl ether and the combined organic phases washed withbrine, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (4:1 chloroform/methanol eluant) to afford the product as alight-brown gum. (31%)

MS (m/z): 386.3 (M+H⁺)

5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid

The title compound was synthesized in analogy to Example 1, Intermediate1b), from5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid ethyl ester, to afford the product as a light-brown gum.

Example 237(4,4-Difluoro-piperidin-1-yl)-[5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to Example 1, from5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid, 4,4-difluoropiperidine hydrochloride, triethylamine and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as a light-brown oil (79%).

MS (m/z): 461.3 (M+H⁺)

Example 238[5-(3-Dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was synthesized in analogy to Example 1, from5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid, thiomorpholine 1,1-dioxide and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as an off-white solid (15%).

MS (m/z): 475.4 (M+H⁺)

Example 239[1-Isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

To a solution of4-[1-isopropyl-2-(morpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (134 mg) in ethyl acetate was added a 5M solutionof hydrogen chloride in ethyl acetate. The mixture was stirred 2 days atroom temperature, and evaporated to dryness to afford the hydrochloridesalt of the deprotected amine as a white solid. The solid was suspendedin 1,2-dichloroethane (5 ml). Triethylamine (0.06 ml), acetone (0.22 ml)and sodium triacetoxyborohydride (171 mg) were added and the mixturestirred 2 days at room temperature. Sodium bicarbonate was added and themixture stirred vigorously. The product was isolated by columnchromatography on silica gel (18:2:0.05 chloroform/methanol/aq ammoniumhydroxide eluant) as a light yellow gum (97%).

MS (m/z): 441.6 (M+H⁺)

Intermediates4-[1-Isopropyl-2-(morpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was synthesized in analogy to Example 1, from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, to afford the product as a yellow solid (91%).

MS (m/z): 499.5 (M+H⁺)

5-(4-tert-Butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid

The title compound was synthesized in analogy to Example 1, Intermediate1b), from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid ethyl ester, to afford the product as an off-white powder (78%).

MS (m/z): 430.5 (M+H⁺)

5-(4-tert-Butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was synthesized in analogy to example 239,Intermediate a), from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester and isopropylmethanesulfonate, to afford the product asa yellow oil (62%).

MS (m/z): 458.5 (M+H⁺)

5-(4-tert-Butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound was synthesized in analogy to Example 1, from1H-indole-2,5-dicarboxylic acid 2-ethyl ester,[1,4]diazepane-1-carboxylic acid tert-butyl ester and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as a white solid (69%).

MS (m/z): 416.5 (M+H⁺)

Example 240(4,4-Difluoro-piperidin-1-yl)-[1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to Example 239, from4-[2-(4,4-difluoro-piperidine-1-carbonyl)-1-isopropyl-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester, to afford the product as a light-yellow gum(88%).

MS (m/z): 475.3 (M+H⁺)

Intermediate4-[2-(4,4-Difluoro-piperidine-1-carbonyl)-1-isopropyl-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was synthesized in analogy to Example 1, from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid, 4,4-difluoropiperidine hydrochloride, triethylamine and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as a yellow solid (70%).

MS (m/z): 533.3 (M+H⁺)

Example 241[5-(4-sec-Butyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to Example 239, from4-[2-(morpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester and 2-butanone, to afford the product as alight-yellow gum (19%).

MS (m/z): 413.5 (M+H⁺)

Intermediates4-[2-(Morpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was synthesized in analogy to Example 1, from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, to afford the product as an off-white solid (99%).

MS (m/z): 457.3 (M+H⁺)

5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid

The title compound was synthesized in analogy to Example 1, Intermediate1b), from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid ethyl ester, to afford the product as a light brown gum (96%).

MS (m/z): 386.4 (M−H)⁻

Example 242(1,1-Dioxo-thiomorpholin-4-yl)-[1-isopropyl-5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to Example 239, from4-[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1-isopropyl-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester, to afford the product as an off-white solid(47%).

MS (m/z): 489.3 (M+H⁺)

Intermediate4-[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1-isopropyl-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was synthesized in analogy to Example 1, from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylicacid, thiomorpholine 1,1-dioxide and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as an off-white solid (85%).

MS (m/z): 547.2 (M+H⁺)

Example 243[5-(4-Isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone

The title compound was synthesized in analogy to Example 239, from4-[2-(morpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester, to afford the product as a white solid (55%).

MS (m/z): 399.3 (M+H⁺)

Example 244(4,4-Difluoro-piperidin-1-yl)-[5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to Example 239, from4-[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester, to afford the product as an orange solid (14%).

MS (m/z): 433.3 (M+H⁺)

Intermediate4-[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was synthesized in analogy to Example 1, from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid, 4,4-difluoropiperidine hydrochloride, triethylamine and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as a yellow solid (87%).

MS (m/z): 491.2 (M+H⁺)

Example 245(1,1-Dioxo-thiomorpholin-4-yl)-[5-(4-isopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-methanone

The title compound was synthesized in analogy to Example 239, from4-[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester, to afford the product as a white solid (68%).

MS (m/z): 447.1 (M+H⁺)

Intermediate4-[2-(1,1-Dioxo-thiomorpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester

The title compound was synthesized in analogy to Example 1, from5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylicacid, thiomorpholine 1,1-dioxide and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to affordthe product as a yellow solid (95%).

MS (m/z): 505.1 (M+H⁺)

Example 246[5-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

To a solution of4-[2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (120 mg) in ethyl acetate (3 ml) was added 5Mmethanolic hydrogen chloride solution. The mixture was stirred overnightat room temperature. The solvent was removed under reduced pressure andthe residue dissolved in methanol. (1-Ethoxycyclopropoxy)trimethylsilane(125 mg) and acetic acid (0.14 ml) were added. Sodium cyanoborohydride(45 mg) was slowly added, and the mixture stirred overnight at roomtemperature. The reaction was quenched by the addition of saturatedaqueous sodium hydrogencarbonate solution. The mixture was extractedwith dichloromethane (3×25 ml), dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (19:1 chloroform/methanol eluant) to affordthe product as an off-white solid (47%).

MS (m/z): 445.3 (M+H⁺)

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavoring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of formula I:

wherein: R¹ is selected from the group consisting of lower alkyl, loweralkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl, lowerhydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lowerdialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted orsubstituted with one to three groups independently selected from loweralkyl, halogen, lower halogenalkoxy and lower hydroxyalkyl, lowerphenylalkyl wherein the phenyl ring may be unsubstituted or substitutedwith one to three groups independently selected from lower alkyl,halogen, lower alkoxy and lower hydroxyalkyl, lower heteroarylalkylwherein the heteroaryl ring may be unsubstituted or substituted with oneor two groups independently selected from lower alkyl, halogen, loweralkoxy and lower hydroxyalkyl, lower heterocyclylalkyl wherein theheterocyclyl ring may be unsubstituted or substituted with one or twogroups selected from lower alkyl and halogen, and7-oxa-bicyclo[2.2.1]heptyl; R² is selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, lowercycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, loweralkylsulfanylalkyl, lower dialkylaminoalkyl, lowerdialkylcarbamoylalkyl, phenyl unsubstituted or substituted with one tothree groups independently selected from lower alkyl, halogen, lowerhalogenalkoxy and lower hydroxyalkyl, lower phenylalkyl wherein thephenyl ring may be unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, lower alkoxy and lowerhydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may beunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,and lower heterocyclylalkyl wherein the heterocycly ring may beunsubstituted or substituted with one or two lower alkyl groups; or R¹and R² together with the nitrogen atom to which they are attached form a4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclicring optionally containing a further heteroatom selected from oxygen orsulfur, a sulfinyl group or a sulfonyl group, said heterocyclic ringbeing unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, halogen, lower halogenalkyl,cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl,pyridyl and carbamoyl, or being condensed with a phenyl ring, saidphenyl ring being unsubstituted or substituted by one, two or threegroups independently selected from lower alkyl, lower alkoxy andhalogen, or R¹ and R² together with the nitrogen atom to which they areattached form a group selected from 1-oxa-8-aza-spiro[4.5]decyl,1,4-dioxa-8-aza-spiro[4.5]decyl and [1,4]oxazepan-7-one; R³ is selectedfrom the group consisting of hydrogen, lower alkyl, cycloalkyl, lowerhydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lowercycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower alkylsulfonyl,phenylsulfonyl wherein the phenyl ring may be unsubstituted orsubstituted with one to three groups independently selected from loweralkyl, halogen, lower alkoxy, lower halogenalkoxy and lowerhydroxyalkyl, phenyl unsubstituted or substituted with one to threegroups independently selected from lower alkyl, halogen, cyano,morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl,lower halogenalkoxy, lower hydroxyalkyl, lower alkylsulfonyl and loweralkylsulfonylamino, benzodioxolyl, lower phenylalkyl, wherein the phenylring may be unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, cyano, morpholinyl,lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl, lowerhalogenalkoxy, lower hydroxyalkyl, lower alkylsulfonyl and loweralkylsulfonylamino, and heteroaryl unsubstituted or substituted with oneor two groups independently selected from lower alkyl, lower alkoxy,cyano, morpholinyl and halogen; R⁴, R¹² and R⁵ are hydrogen, or one ofR⁴, R¹² and R⁵ is halogen and the other ones are hydrogen; G is

wherein m is 1 or 2; R⁸ is hydrogen or lower heterocyclylalkyl; R⁹ ishydrogen or —NR¹⁰R¹¹; R¹⁰ and R¹¹ independently from each other arelower alkyl or together with the nitrogen atom to which they areattached form a 5- or 6-membered saturated heterocyclic ring optionallycontaining a further heteroatom selected from nitrogen, oxygen orsulfur; R¹³ is hydrogen or —NR¹⁰R¹¹; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein R¹ isselected from the group consisting of lower alkyl, lower alkenyl, loweralkinyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, loweralkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, lowerdialkylcarbamoylalkyl, phenyl unsubstituted or substituted with one tothree groups independently selected from lower alkyl, halogen, lowerhalogenalkoxy and lower hydroxyalkyl, lower phenylalkyl wherein thephenyl ring may be unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, lower alkoxy and lowerhydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may beunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,lower heterocyclylalkyl wherein the heterocyclyl ring may beunsubstituted or substituted with one or two groups selected from loweralkyl and halogen, and 7-oxa-bicyclo[2.2.1]heptyl; and R² is hydrogen orlower alkyl.
 3. The compound according to claim 1, wherein R¹ isselected from the group consisting of cycloalkyl, phenyl unsubstitutedor substituted with one to three groups independently selected fromlower alkyl, halogen, lower halogenalkoxy and lower hydroxyalkyl, lowerphenylalkyl wherein the phenyl ring may be unsubstituted or substitutedwith one to three groups independently selected from lower alkyl,halogen, lower alkoxy and lower hydroxyalkyl, and lowerheterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted orsubstituted with one or two groups selected from lower alkyl andhalogen; and R² is hydrogen or lower alkyl.
 4. The compound according toclaim 1, wherein R¹ and R² together with the nitrogen atom to which theyare attached form a 4-, 5-, 6- or 7-membered saturated or partlyunsaturated heterocyclic ring optionally containing a further heteroatomselected from oxygen or sulfur, a sulfinyl group or a sulfonyl group,said heterocyclic ring being unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, halogen, lowerhalogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo,phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenylring, said phenyl ring being unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, lower alkoxy andhalogen, or R¹ and R² together with the nitrogen atom to which they areattached form a group selected from 1-oxa-8-aza-spiro[4.5]decyl,1,4-dioxa-8-aza-spiro[4.5]decyl and [1,4]oxazepan-7-one.
 5. The compoundaccording to claim 1, wherein R¹ and R² together with the nitrogen atomto which they are attached form a heterocyclic ring selected from thegroup consisting of morpholine, piperidine, 2,5-dihydropyrrole,pyrrolidine, azepane, piperazine, azetidine, thiomorpholine,1,1-dioxothiomorpholine and 3,6-dihydro-2H-pyridine, said heterocyclicring being unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, halogen, lower halogenalkyl,cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl,pyridyl and carbamoyl, or being condensed with a phenyl ring, saidphenyl ring being unsubstituted or substituted by one, two or threegroups independently selected from lower alkyl, lower alkoxy andhalogen, or wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a group selected from1-oxa-8-aza-spiro[4.5]decyl, 1,4-dioxa-8-aza-spiro[4.5]decyl and[1,4]oxazepan-7-one.
 6. The compound according to claim 1, wherein R¹and R² together with the nitrogen atom to which they are attached form aheterocyclic ring selected from the group consisting of morpholine,thiomorpholine, 1,1-dioxothiomorpholine, pyrrolidine, piperidine andazepane, said heterocyclic ring being unsubstituted or substituted byone, two or three groups independently selected from lower alkyl,halogen, lower halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, loweralkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensedwith a phenyl ring, said phenyl ring being unsubstituted or substitutedby one, two or three groups independently selected from lower alkyl,lower alkoxy and halogen, or wherein R¹ and R² together with thenitrogen atom to which they are attached form a1,4-dioxa-8-aza-spiro[4.5]decyl group.
 7. The compound according toclaim 1, wherein R¹ and R² together with the nitrogen atom to which theyare attached form a heterocyclic ring selected from the group consistingof morpholine, thiomorpholine, 1,1-dioxothio-morpholine, pyrrolidine,piperidine and 4,4-difluoropiperidinyl.
 8. The compound according toclaim 1, wherein R³ is selected from the group consisting of hydrogen,lower alkyl, cycloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lowerhalogenalkyl, lower cycloalkylalkyl, lower cyanoalkyl, loweralkylsulfonyl, phenyl unsubstituted or substituted with one to threegroups independently selected from lower alkyl, halogen, cyano,morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl,lower halogenalkoxy, lower hydroxyalkyl, lower alkylsulfonyl and loweralkylsulfonylamino, benzodioxolyl, lower phenylalkyl, wherein the phenylring may be unsubstituted or substituted with one to three groupsindependently selected from lower alkyl, halogen, cyano, morpholinyl,lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl, lowerhalogenalkoxy, lower hydroxyalkyl, lower alkylsulfonyl and loweralkylsulfonylamino, and heteroaryl unsubstituted or substituted with oneor two groups independently selected from lower alkyl, lower alkoxy,cyano, morpholinyl and halogen.
 9. The compound according to claim 1,wherein R³ is selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lowerhalogenalkyl, lower cycloalkylalkyl, lower cyanoalkyl and loweralkylsulfonyl.
 10. The compound according to claim 1, wherein R³ islower alkyl or lower halogenalkyl.
 11. The compound according to claim1, wherein R³ is phenyl unsubstituted or substituted with one to threegroups independently selected from lower alkyl, halogen, cyano,morpholinyl, lower alkoxy, lower alkoxycarbonyl, lower halogenalkyl,lower halogenalkoxy, lower alkylsulfonyl and lower alkylsulfonylamino,benzodioxolyl, or lower phenylalkyl, wherein the phenyl ring may beunsubstituted or substituted with one to three groups independentlyselected from halogen, cyano or lower halogenalkyl.
 12. The compoundaccording to claim 1, wherein R³ is unsubstituted phenyl or phenylsubstituted with one to three groups independently selected fromhalogen, cyano or lower halogenalkyl.
 13. The compound according toclaim 1, wherein R³ is heteroaryl selected from pyridyl or pyrimidinyl,said heteroaryl being unsubstituted or substituted with one or twogroups independently selected from lower alkyl, lower alkoxy, cyano,morpholinyl and halogen.
 14. The compound according to claim 1, whereinR⁴, R¹² and R⁵ are hydrogen.
 15. The compound according to claim 1,wherein R⁸ is hydrogen, R⁹ is —NR¹⁰R¹¹, R¹³ is hydrogen and R¹⁰ and R¹¹independently from each other are lower alkyl or together with thenitrogen atom to which they are attached form a 5- or 6-memberedsaturated heterocyclic ring optionally containing a further heteroatomselected from nitrogen, oxygen or sulfur.
 16. The compound according toclaim 1, wherein R⁸ is lower heterocyclylalkyl and R⁹ is hydrogen.
 17. Apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to claim 1 as well as a pharmaceuticallyacceptable carrier and/or adjuvant.